seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   1 MDMQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAII 80
Cdd:cd15125   106 MDIQTSSAVLRTCLKAIAIWVVSVLLAVPEAVFSEVAHIMPDDNTTFTACIPYPQTDEMHPKIHSVLIFLVYFLIPLAII 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  81 SIYYYHIAKTLIKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLV 160
Cdd:cd15125   186 SIYYYHIAKTLIKSAHNIPGEYSEHSKRQMETRKRLAKIVLVFVGLFAFCWFPNHVLYMYRSFNYNEIDSSLGHMIVTLV 265

                         170       180
                  ....*....|....*....|....*..
gi 1024249356 161 ARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15125   266 ARVLSFCNSCVNPFALYLLSESFRRHF 292

neuromedin B receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The neuromedin B receptor (NMBR), also known as BB1, is a G-protein coupled receptor whose endogenous ligand is the neuropeptide neuromedin B. Neuromedin B is a potent mitogen and growth factor for normal and cancerous lung and for gastrointestinal epithelial tissues. NMBR is widely distributed in the CNS, with especially high levels in olfactory nucleus and thalamic regions. The receptor couples primarily to a pertussis-toxin-insensitive G protein of the Gq/11 family, which leads to the activation of phospholipase C. NMBR belongs to the bombesin subfamily of G-protein coupled receptors, whose members also include gastrin-releasing peptide receptor (GRPR) and bombesin receptor subtype 3 (BRS-3). Bombesin is a tetradecapeptide, originally isolated from frog skin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   1 MDMQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAII 80
Cdd:cd15125   106 MDIQTSSAVLRTCLKAIAIWVVSVLLAVPEAVFSEVAHIMPDDNTTFTACIPYPQTDEMHPKIHSVLIFLVYFLIPLAII 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  81 SIYYYHIAKTLIKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLV 160
Cdd:cd15125   186 SIYYYHIAKTLIKSAHNIPGEYSEHSKRQMETRKRLAKIVLVFVGLFAFCWFPNHVLYMYRSFNYNEIDSSLGHMIVTLV 265

                         170       180
                  ....*....|....*....|....*..
gi 1024249356 161 ARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15125   266 ARVLSFCNSCVNPFALYLLSESFRRHF 292

G protein-coupled chemokine receptor-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  10 LRTCVKAMGIWVVSVLLAVPEAVFSEVARisslDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAK 89
Cdd:PHA03087  153 KYGYIVSLVIWIISIIETTPILFVYTTKK----DHETLICCMFYNNKTMNWKLFINFEINIIGMLIPLTILLYCYSKILI 228

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  90 TLIKSAHNlpgeynehTKKqmetrKRLAKIVLVFVGCFIFCWFPNH---ILYMYRSFNYNEIDPSLGHMIVTL-VARVLS 165
Cdd:PHA03087  229 TLKGINKS--------KKN-----KKAIKLVLIIVILFVIFWLPFNvsvFVYSLHILHFKSGCKAVKYIQYALhVTEIIS 295

                         170       180
                  ....*....|....*....|.
gi 1024249356 166 FGNSCVNPFALYLLSESFRRH 186
Cdd:PHA03087  296 LSHCCINPLIYAFVSEFFNKH 316

neuromedin B receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The neuromedin B receptor (NMBR), also known as BB1, is a G-protein coupled receptor whose endogenous ligand is the neuropeptide neuromedin B. Neuromedin B is a potent mitogen and growth factor for normal and cancerous lung and for gastrointestinal epithelial tissues. NMBR is widely distributed in the CNS, with especially high levels in olfactory nucleus and thalamic regions. The receptor couples primarily to a pertussis-toxin-insensitive G protein of the Gq/11 family, which leads to the activation of phospholipase C. NMBR belongs to the bombesin subfamily of G-protein coupled receptors, whose members also include gastrin-releasing peptide receptor (GRPR) and bombesin receptor subtype 3 (BRS-3). Bombesin is a tetradecapeptide, originally isolated from frog skin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   1 MDMQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAII 80
Cdd:cd15125   106 MDIQTSSAVLRTCLKAIAIWVVSVLLAVPEAVFSEVAHIMPDDNTTFTACIPYPQTDEMHPKIHSVLIFLVYFLIPLAII 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  81 SIYYYHIAKTLIKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLV 160
Cdd:cd15125   186 SIYYYHIAKTLIKSAHNIPGEYSEHSKRQMETRKRLAKIVLVFVGLFAFCWFPNHVLYMYRSFNYNEIDSSLGHMIVTLV 265

                         170       180
                  ....*....|....*....|....*..
gi 1024249356 161 ARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15125   266 ARVLSFCNSCVNPFALYLLSESFRRHF 292

gastrin-releasing peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The gastrin-releasing peptide receptor (GRPR) is a G-protein coupled receptor whose endogenous ligand is gastrin releasing peptide. GRP shares high sequence homology with the neuropeptide neuromedin B in the C-terminal region. This receptor is high glycosylated and couples to a pertussis-toxin-insensitive G protein of the family of Gq/11, which leads to the activation of phospholipase C. Gastrin-releasing peptide (GRP) is a potent mitogen for neoplastic tissues and involved in regulating multiple functions of the gastrointestinal and central nervous systems. These include the release of gastrointestinal hormones, the contraction of smooth muscle cells, and the proliferation of epithelial cells. GRPR belongs to the bombesin subfamily of G-protein coupled receptors, whose members also include neuromedin B receptor (NMBR) and bombesin receptor subtype 3 (BRS-3). Bombesin is a tetradecapeptide, originally isolated from frog skin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   1 MDMQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLD-NSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAI 79
Cdd:cd15124   106 MDIQASNALMKICLKAALIWILSMLLAIPEAVFSDLHPFYDKStNKTFVSCAPYPHSNELHPKIHSMASFLIFYVIPLSI 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  80 ISIYYYHIAKTLIKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTL 159
Cdd:cd15124   186 ISVYYYFIAKNLIRSAYNLPVEGNVHVRRQIESRKRLAKTVLVFVGLFAFCWLPNHIIYLYRSYHYSEVDTSMLHFVSSI 265

                         170       180
                  ....*....|....*....|....*...
gi 1024249356 160 VARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15124   266 CARILAFTNSCVNPFALYLLSKSFRKQF 293

bombesin receptor subtype 3, member of the class A family of seven-transmembrane G protein-coupled receptors; BRS-3 is classified as an orphan receptor and belongs to the bombesin subfamily of G-protein coupled receptors, whose members also include neuromedin B receptor (NMBR) and gastrin-releasing peptide receptor (GRPR). Bombesin is a tetradecapeptide, originally isolated from frog skin. Mammalian bombesin-related peptides are widely distributed in the gastrointestinal and central nervous systems. The bombesin family receptors couple primarily to the G proteins of G(q/11) family. BRS-3 interacts with known naturally-occurring bombesin-related peptides with low affinity; however, no endogenous high-affinity ligand to the receptor has been identified. BRS-3 is suggested to play a role in sperm cell division and maturation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   1 MDMQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLD-NSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAI 79
Cdd:cd15123   106 LELQTSDAVLKTCCKAGCVWIVSMLFAIPEAVFSDLYSFRDPEkNTTFEACAPYPVSEKILQEIHSLLCFLVFYIIPLSI 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  80 ISIYYYHIAKTLIKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNE-IDPSLGHMIVT 158
Cdd:cd15123   186 ISVYYFLIARTLYKSTFNMPAEEHSHARKQIESRKRVAKTVLVLVALFAFCWLPNHILYLYRSFTYHTsVDSSAFHLIAT 265

                         170       180
                  ....*....|....*....|....*....
gi 1024249356 159 LVARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15123   266 IFSRVLAFSNSCVNPFALYWLSKSFRQHF 294

7 transmembrane receptor (rhodopsin family); This family contains, amongst other G-protein-coupled receptors (GCPRs), members of the opsin family, which have been considered to be typical members of the rhodopsin superfamily. They share several motifs, mainly the seven transmembrane helices, GCPRs of the rhodopsin superfamily. All opsins bind a chromophore, such as 11-cis-retinal. The function of most opsins other than the photoisomerases is split into two steps: light absorption and G-protein activation. Photoisomerases, on the other hand, are not coupled to G-proteins - they are thought to generate and supply the chromophore that is used by visual opsins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  11 RTCVKAMGIWVVSVLLAVPEAVFSEVariSSLDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKT 90
Cdd:pfam00001 101 RAKVLILVIWVLALLLSLPPLLFGWT---LTVPEGNVTVCFIDFPEDLSKPVSYTLLISVLGFLLPLLVILVCYTLIIRT 177

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  91 LIKSAHnlpgeyNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNyNEIDPSLGHMIVTLVARVLSFGNSC 170
Cdd:pfam00001 178 LRKSAS------KQKSSERTQRRRKALKTLAVVVVVFILCWLPYHIVNLLDSLA-LDCELSRLLDKALSVTLWLAYVNSC 250

                  ....
gi 1024249356 171 VNPF 174
Cdd:pfam00001 251 LNPI 254

rhodopsin receptor-like class A family of the seven-transmembrane G protein-coupled receptor superfamily; Class A rhodopsin-like receptors constitute about 90% of all GPCRs. The class A GPCRs include the light-sensitive rhodopsin as well as receptors for biogenic amines, lipids, nucleotides, odorants, peptide hormones, and a variety of other ligands. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. Based on sequence similarity, GPCRs can be divided into six major classes: class A (rhodopsin-like family), class B (Methuselah-like, adhesion and secretin-like receptor family), class C (metabotropic glutamate receptor family), class D (fungal mating pheromone receptors), class E (cAMP receptor family), and class F (frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  18 GIWVVSVLLAVPEAVFSEVarisslDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKTLIKSAHN 97
Cdd:cd00637   121 LIWLLSLLLALPPLLGWGV------YDYGGYCCCCLCWPDLTLSKAYTIFLFVLLFLLPLLVIIVCYVRIFRKLRRHRRR 194

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1024249356  98 LPGEY-NEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYneiDPSLGHMIVTLVARVLSFGNSCVNPF 174
Cdd:cd00637   195 IRSSSsNSSRRRRRRRERKVTKTLLIVVVVFLLCWLPYFILLLLDVFGP---DPSPLPRILYFLALLLAYLNSAINPI 269

angiotesin receptor family and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the angiotensin receptors, the bradykinin receptors, apelin receptor as well as putative G-protein coupled receptors (GPR15 and GPR25). Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors. Ang II contributes to cardiovascular diseases such as hypertension and atherosclerosis via AT1R activation. Ang II increases blood pressure through Gq-mediated activation of phospholipase C, resulting in phosphoinositide (PI) hydrolysis and increased intracellular calcium levels. Through the AT2 receptor, Ang II counteracts the vasoconstrictor action of AT1R and thereby induces vasodilation, sodium excretion, and reduction of blood pressure. Bradykinins (BK) are pro-inflammatory peptides that mediate various vascular and pain responses to tissue injury through its B1 and B2 receptors. Apelin (APJ) receptor binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body, and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake. Orphan receptors, GPR15 and GPR25, share strong sequence homology to the angiotensin II type AT1 and AT2 receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  18 GIWVVSVLLAVPEAVFSEVARISSLDNssfTACIPYPQTDELHPKIhSVLIFLVYFLIPLAIISIYYYHIAKTLIKSahn 97
Cdd:cd14985   123 LIWVVACLLSLPTFLLRSLQAIENLNK---TACIMLYPHEAWHFGL-SLELNILGFVLPLLIILTCYFHIARSLRKR--- 195

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  98 lpgeyNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHIL-YMYRSFNYNEIDPSLGHMIVTL---VARVLSFGNSCVNP 173
Cdd:cd14985   196 -----YERTGKNGRKRRKSLKIIFALVVAFLVCWLPFHFFkFLDFLAQLGAIRPCFWELFLDLglpIATCLAFTNSCLNP 270

                         170
                  ....*....|....
gi 1024249356 174 FALYLLSESFRRHF 187
Cdd:cd14985   271 FIYVFVDRRFRQKV 284

neuropeptide FF receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Neuropeptide FF (NPFF) is a mammalian octapeptide that belongs to a family of neuropeptides containing an RF-amide motif at their C-terminus that have been implicated in a wide range of physiological functions in the brain including pain sensitivity, insulin release, food intake, memory, blood pressure, and opioid-induced tolerance and hyperalgesia. The effects of these peptides are mediated through neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R) which are predominantly expressed in the brain. NPFF induces pro-nociceptive effects, mainly through the NPFF1-R, and anti-nociceptive effects, mainly through the NPFF2-R. NPFF has been shown to inhibit adenylate cyclase via the Gi protein coupled to NPFF1-R.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  11 RTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDElHPKIHSVLIFLVYFLIPLAIISIYYYHIAKT 90
Cdd:cd15207   114 QAFVIIVAIWVLALAIMIPQALVLEVKEYQFFRGQTVHICVEFWPSDE-YRKAYTTSLFVLCYVAPLLIIAVLYVRIGYR 192

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  91 L-IKSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSF-NYNEIDPSLGHMIVTLVARVLSFGN 168
Cdd:cd15207   193 LwFKPVPGGGSASREAQAAVSKKKVRVIKMLIVVVVLFALSWLPLHTVTMLDDFgNLSPNQREVLYVYIYPIAHWLAYFN 272

                         170
                  ....*....|....*....
gi 1024249356 169 SCVNPFALYLLSESFRRHF 187
Cdd:cd15207   273 SCVNPIVYGYFNRNFRKGF 291

orexin receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Orexins (OXs, also referred to as hypocretins) are neuropeptide hormones that regulate the sleep-wake cycle and potently influence homeostatic systems regulating appetite and feeding behavior or modulating emotional responses such as anxiety or panic. OXs are synthesized as prepro-orexin (PPO) in the hypothalamus and then proteolytically cleaved into two forms of isoforms: orexin-A (OX-A) and orexin-B (OX-B). OXA is a 33 amino-acid peptide with N-terminal pyroglutamyl residue and two intramolecular disulfide bonds, whereas OXB is a 28 amino-acid linear peptide with no disulfide bonds. OX-A binds orexin receptor 1 (OX1R) with high-affinity, but also binds with somewhat low-affinity to OX2R, and signals primarily to Gq coupling, whereas OX-B shows a strong preference for the orexin receptor 2 (OX2R) and signals through Gq or Gi/o coupling. Thus, activation of OX1R or OX2R will activate phospholipase activity and the phosphatidylinositol and calcium signaling pathways. Additionally, OX2R activation can also lead to inhibition of adenylate cyclase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  11 RTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDN--SSFTACipYPQ-TDELHPKIHSVLIFLVYFLIPLAIISIYYYHI 87
Cdd:cd15208   114 RARVSILIIWIVSLLIMIPQAIVMECSRVVPLANktILLTVC--DERwSDSIYQKVYHICFFLVTYLLPLCLMILAYFQI 191

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  88 AKTL-----------IKSAHNLPGEYNEHTK-KQMETRKRLAKIVLVFVGCFIFCWFPNHIL-YMYRSFNYNEIDPSLGH 154
Cdd:cd15208   192 FRKLwcrqipgtssvVQRKWNKPRKSAVAAEeKQLRSRRKTAKMLIVVVIMFAICYLPVHLLnILRYVFGLFTVDRETIY 271

                         170       180       190
                  ....*....|....*....|....*....|...
gi 1024249356 155 mIVTLVARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15208   272 -AWFLFSHWLVYANSAINPIIYNFMSGKFREEF 303

tachykinin receptor and closely related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes G-protein coupled receptors for a variety of neuropeptides of the tachykinin (TK) family as well as closely related receptors. The tachykinins are widely distributed throughout the mammalian central and peripheral nervous systems and act as excitatory transmitters on neurons and cells in the gastrointestinal tract. The TKs are characterized by a common five-amino acid C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is a hydrophobic residue. The three major mammalian tachykinins are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). The physiological actions of tachykinins are mediated through three types of receptors: neurokinin receptor type 1 (NK1R), NK2R, and NK3R. SP is a high-affinity endogenous ligand for NK1R, which interacts with the Gq protein and activates phospholipase C, leading to elevation of intracellular calcium. NK2R is a high-affinity receptor for NKA, the tachykinin neuropeptide substance K. SP and NKA are found in the enteric nervous system and mediate in the regulation of gastrointestinal motility, secretion, vascular permeability, and pain perception. NK3R is activated by its high-affinity ligand, NKB, which is primarily involved in the central nervous system and plays a critical role in the regulation of gonadotropin hormone release and the onset of puberty.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  19 IWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQ-TDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKTLIKSahN 97
Cdd:cd14992   124 IWVVSLLLAIPQLYYATTEVLFSVKNQEKIFCCQIPPvDNKTYEKVYFLLIFVVIFVLPLIVMTLAYARISRELWFR--K 201

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  98 LPGE-YNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNeIDPSLGHMIVTLVARVLSFGNSCVNPFAL 176
Cdd:cd14992   202 VPGFsIKEVERKRLKCKRRVIKMLVCVVVLFVICWLPFHLFFLLRDFFPL-IMKEKHTLQVYYFLHWIAMSNSMYNPIIY 280

                         170
                  ....*....|.
gi 1024249356 177 YLLSESFRRHF 187
Cdd:cd14992   281 VTLNNNFRKNF 291

classical and atypical chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. In addition to these classical chemokine receptors, there exists a subfamily of atypical chemokine receptors (ACKRs) that are unable to couple to G-proteins and, instead, they preferentially mediate beta-arrestin dependent processes, such as receptor internalization, after ligand binding. The classical chemokine receptors contain a conserved DRYLAIV motif in the second intracellular loop, which is required for G-protein coupling. However, the ACKRs lack this conserved motif and fail to couple to G-proteins and induce classical GPCR signaling. Five receptors have been identified for the ACKR family, including CC-chemokine receptors like 1 and 2 (CCRL1 and CCRL2), CXCR7, Duffy antigen receptor for chemokine (DARC), and D6. Both ACKR1 (DARC) and ACKR3 (CXCR7) show low sequence homology to the classic chemokine receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   9 LLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNssftaCIP-YPQTDELHPKI-HSVLIFLVYFLIPLAIISIYYYH 86
Cdd:cd14984   112 LLHGKLTCLGVWALALLLSLPEFIFSQVSEENGSSI-----CSYdYPEDTATTWKTlLRLLQNILGFLLPLLVMLFCYSR 186

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  87 IAKTLIKSahnlpgeynehtkkQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFN-YNEIDPSLGHM----IVTLVA 161
Cdd:cd14984   187 IIRTLLRA--------------RNHKKHRALRVIFAVVVVFFLCWLPYNIVLLLDTLQlLGIISRSCELSksldYALQVT 252

                         170       180
                  ....*....|....*....|....*.
gi 1024249356 162 RVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd14984   253 ESLAFSHCCLNPVLYAFVGVKFRKYL 278

neuropeptide capa receptor and similar invertebrate proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; CapaR is a G-protein coupled receptor for the Drosophila melanogaster capa neuropeptides (Drm-capa-1 and -2), which act on the Malpighian tubules to increase fluid transport. The capa peptides are evolutionarily related to vertebrate Neuromedin U neuropeptide and contain a C-terminal FPRXamide motif. CapaR regulates fluid homeostasis through its ligands, thereby acts as a desiccation stress-responsive receptor. CapaR undergoes desensitization, with internalization mediated by beta-arrestin-2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   4 QTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFT-----ACIPYPQTDELHPKIHsvLIFLVYFLIPLA 78
Cdd:cd15134   110 HTMSKLSRAIRIIIAIWIIAFVCALPFAIQTRIVYLEYPPTSGEAleesaFCAMLNEIPPITPVFQ--LSTFLFFIIPMI 187

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  79 IISIYYYHIAKTLIKSAHNLPGEYNEH-TKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSL-GHMI 156
Cdd:cd15134   188 AIIVLYVLIGLQLRRSTLLRRGQRSVSgGRRSSQSRRTVLRMLVAVVVAFFICWAPFHAQRLLTVYAKNMTPPYLfINRI 267

                         170       180       190
                  ....*....|....*....|....*....|.
gi 1024249356 157 VTLVARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15134   268 LFYISGVLYYVSSTVNPILYNVMSAKYRQAF 298

endothelin C receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C, and phospholipase D, as well as cytosolic protein kinase activation. They play an important role in the regulation of the cardiovascular system and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels. Two endothelin receptor subtypes have been isolated and identified in vertebrates, endothelin A receptor (ET-A) and endothelin B receptor (ET-B), and are members of the seven transmembrane class A G-protein coupled receptor family which activate multiple effectors via different types of G protein. Some vertebrates contain a third subtype, endothelin A receptor (ET-C). ET-A receptors are mainly located on vascular smooth muscle cells, whereas ET-B receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain. The ET-C receptor is specific for endothelin-3 on frog dermal melanophores; its activation causes dispersion of pigment granules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356   3 MQTSGALLRTCVKAMGIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDEL---HPKIHSVLIFLVYFLIPLAI 79
Cdd:cd15977   108 IRGIGIPVWKAVEVTLIWAVAIIVAVPEAIAFDMVEIDYRGQTLLVCMLPMEQTSSFmrfYQDVKDWWLFGFYFCLPLAC 187

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  80 ISIYYYHIAKTLIKSAHNLPGEYNEHtkkqMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGH----- 154
Cdd:cd15977   188 TGVFYTLMSCEMLSIKNGMRIALNDH----MKQRREVAKTVFCLVVIFALCWLPLHLSRILKKTIYDVKDPQRCEllsfl 263

                         170       180       190
                  ....*....|....*....|....*....|...
gi 1024249356 155 MIVTLVARVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15977   264 LVMDYTGINMASLNSCINPVALYFVSRKFKNCF 296

opioid receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes opioid receptors, somatostatin receptors, melanin-concentrating hormone receptors (MCHRs), and neuropeptides B/W receptors. Together they constitute the opioid receptor-like family, members of the class A G-protein coupled receptors. Opioid receptors are coupled to inhibitory G proteins of the G(i/o) family and are involved in regulating a variety of physiological functions such as pain, addiction, mood, stress, epileptic seizure, and obesity, among many others. G protein-coupled somatostatin receptors (SSTRs), which display strong sequence similarity with opioid receptors, binds somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. MCHR binds melanin concentrating hormone and is presumably involved in the neuronal regulation of food intake. Despite strong homology with somatostatin receptors, MCHR does not appear to bind somatostatin. Neuropeptides B/W receptors are primarily expressed in the CNS and stimulate the cortisol secretion by activating the adenylate cyclase- and the phospholipase C-dependent signaling pathways.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  10 LRTCVKA----MGIWVVSVLLAVPEAVFSEVARISSlDNSSFTACIP-YPQTDELHPKIHSvliFLVYFLIPLAIISIYY 84
Cdd:cd14970   110 FRTPRKAklvsLCVWALSLVLGLPVIIFARTLQEEG-GTISCNLQWPdPPDYWGRVFTIYT---FVLGFAVPLLVITVCY 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  85 YHIAKTLiKSAHNLPgeyNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNynEIDPSLGHMIVTLVARVL 164
Cdd:cd14970   186 SLIIRRL-RSSRNLS---TSGAREKRRARRKVTRLVLVVVAVFVVCWLPFHVFQIVRLLI--DPPETLTVVGVFLFCIAL 259

                         170       180
                  ....*....|....*....|...
gi 1024249356 165 SFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd14970   260 SYANSCLNPILYAFLDENFRKSF 282

anaphylatoxin receptors and related G protein-coupled chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily of G-protein coupled receptors includes anaphylatoxin receptors, formyl peptide receptors (FPR), prostaglandin D2 receptor 2, GPR1, and related chemokine receptors. The anaphylatoxin receptors are a group of G-protein coupled receptors that bind anaphylatoxins. The members of this group include C3a and C5a receptors. The formyl peptide receptors (FPRs) are chemoattractant GPCRs that involved in mediating immune responses to infection. They are expressed mainly on polymorphonuclear and mononuclear phagocytes and bind N-formyl-methionyl peptides (FMLP), which are derived from the mitochondrial proteins of ruptured host cells or invading pathogens. Chemokine receptor-like 1 (also known as chemerin receptor 23) is a GPCR for the chemoattractant adipokine chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with chemerin induces activation of the MAPK and PI3K signaling pathways leading to downstream functional effects, such as a decrease in immune responses, stimulation of adipogenesis, and angiogenesis. On the other hand, resolvin E1 negatively regulates the cytokine production in macrophages by reducing the activation of MAPK1/3 and NF-kB pathways. Prostaglandin D2 receptor, also known as CRTH2, is a chemoattractant G-protein coupled receptor expressed on T helper type 2 cells that binds prostaglandin D2 (PGD2). PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses and also causes vasodilation. PGD2 exerts its inflammatory effects by binding to two G-protein coupled receptors, the D-type prostanoid receptor (DP) and PD2R2 (CRTH2). PD2R2 couples to the G protein G(i/o) type which leads to a reduction in intracellular cAMP levels and an increase in intracellular calcium. GPR1 is an orphan receptor that can be activated by the leukocyte chemoattractant chemerin, thereby suggesting that some of the anti-inflammatory actions of chemerin may be mediated through GPR1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  13 CVKAMGIWVVSVLLAVPEAVFSEVArissLDNSSFTACIPYPQTDELHPKIHSVLI---FLVYFLIPLAIISIYYYHIAK 89
Cdd:cd14974   117 SVVCVGIWILALVLSVPYFVFRDTV----THHNGRSCNLTCVEDYDLRRSRHKALTvirFLCGFLLPLLIIAICYSVIAV 192

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  90 TLiksahnlpgeynehTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLghMIVTLVARVLSFGNS 169
Cdd:cd14974   193 KL--------------RRKRLAKSSKPLRVLLAVVVAFFLCWLPYHVFALLELVAAAGLPEVV--LLGLPLATGLAYFNS 256

                         170
                  ....*....|....*....
gi 1024249356 170 CVNPFaLYLL-SESFRRHF 187
Cdd:cd14974   257 CLNPI-LYVFmGQDFRKRL 274

prolactin-releasing peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Prolactin-releasing peptide (PrRP) receptor (previously known as GPR10) is expressed in the central nervous system with the highest levels located in the anterior pituitary and is activated by its endogenous ligand PrRP, a neuropeptide possessing a C-terminal Arg-Phe-amide motif. There are two active isoforms of PrRP in mammals: one consists of 20 amino acids (PrRP-20) and the other consists of 31 amino acids (PrRP-31), where PrRP-20 is a C-terminal fragment of PrRP-31. Binding of PrRP to the receptor coupled to G(i/o) proteins activates the extracellular signal-related kinase (ERK) and it can also couple to G(q) protein leading to an increase in intracellular calcium and activation of c-Jun N-terminal protein kinase (JNK). The PrRP receptor shares significant sequence homology with the neuropeptide Y (NPY) receptor, and micromolar levels of NPY can bind and completely inhibit the PrRP-evoked intracellular calcium response in PrRP receptor-expressing cells, suggesting that the PrRP receptor shares a common ancestor with the NPY receptors. PrRP has been shown to reduce food intake and body weight and modify body temperature when administered in rats. It also has been shown to decrease circulating growth hormone levels by activating somatostatin-secreting neurons in the hypothalamic periventricular nucleus.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  10 LRTCVKAM-GIWVVSVLLAVPEAVFSEVARISSLDnssFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIA 88
Cdd:cd15394   113 RRTCAYIVaAIWLLSCGLALPAAAHTYYVEFKGLD---FSICEEFWFGQEKQRLAYACSTLLITYVLPLLAISLSYLRIS 189

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  89 KTLikSAHNLPGE-YNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIvTLVARVLSFG 167
Cdd:cd15394   190 VKL--RNRVVPGSmTQSQAEWDRARRRKTFRLLVVVVVAFAICWLPLHIFNVIRDIDIDLIDKQYFNLI-QLLCHWLAMS 266

                         170
                  ....*....|....*....
gi 1024249356 168 NSCVNPFALYLLSESFRRH 186
Cdd:cd15394   267 SACYNPFLYAWLHDSFRGE 285

amine receptors and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; Amine receptors of the class A family of GPCRs include adrenoceptors, 5-HT (serotonin) receptors, muscarinic cholinergic receptors, dopamine receptors, histamine receptors, and trace amine receptors. The receptors of amine subfamily are major therapeutic targets for the treatment of neurological disorders and psychiatric diseases. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  11 RTCVKAMGIWVVSVLLAVPeAVFSEvaRISSLDNSSFTACIPYPQtdelhpKIHSVLIFLVYFLIPLAIISIYYYHIAKT 90
Cdd:cd14967   115 RALIMIAAVWVYSLLISLP-PLVGW--RDETQPSVVDCECEFTPN------KIYVLVSSVISFFIPLLIMIVLYARIFRV 185

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  91 LIKSahnlpgeynehtkkqmetrKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLvarvLSFGNSC 170
Cdd:cd14967   186 ARRE-------------------LKAAKTLAIIVGAFLLCWLPFFIIYLVSAFCPPDCVPPILYAVFFW----LGYLNSA 242

                         170
                  ....*....|....*..
gi 1024249356 171 VNPFALYLLSESFRRHF 187
Cdd:cd14967   243 LNPIIYALFNRDFRRAF 259

G protein-coupled receptor 151, member of the class A family of seven-transmembrane G protein-coupled receptors; G-protein coupled receptor 151 (GRP151) is an orphan receptor of unknown function. Its expression is conserved in habenular axonal projections of vertebrates and may be a promising novel target for psychiatric drug development. GPR151 shows high sequence similarity with galanin receptors (GALR). GPR151 is a member of the class A rhodopsin-like GPCRs, which represent a widespread protein family that includes the light-sensitive rhodopsin as well as receptors for biogenic amines, lipids, nucleotides, odorants, peptide hormones, and a variety of other ligands. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  11 RTCVKAMGIWVVSVLLAVPEAVFSEVARisSLDNSSFTACIPYP-QTDELhpkIHSVLIFLVYFLIPLAIISIYYYHIAK 89
Cdd:cd15002   116 RITAVVASIWVPACLLPLPQWLFRTVKQ--SEGVYLCILCIPPLaHEFMS---AFVKLYPLFVFCLPLTFALFYFWRAYG 190

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  90 TLIKSAhnlpgeynehTKKQMET----RKRLAKIVLVFVGCFIFCWFPNHILYMY----RSFNYNeidpslGHMIVTLVA 161
Cdd:cd15002   191 QCQRRG----------TKTQNLRnqirSRKLTHMLLSVVLAFTILWLPEWVAWLWlihiKSSGSS------PPQLFNVLA 254

                         170       180
                  ....*....|....*....|....*.
gi 1024249356 162 RVLSFGNSCVNPFALYLLSESFRRHF 187
Cdd:cd15002   255 QLLAFSISSVNPIIFLLMSEEFREGF 280

neuropeptide Y receptor-like found in insect and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes a novel G protein-coupled receptor (also known as PR4 receptor) from Drosophila melanogaster, which can be activated by the members of the neuropeptide Y (NPY) family, including NPY, peptide YY (PYY) and pancreatic polypeptide (PP), when expressed in Xenopus oocytes. These homologous peptides of 36-amino acids in length contain a hairpin-like structural motif, which referred to as the pancreatic polypeptide fold, and function as gastrointestinal hormones and neurotransmitters. The PR4 receptor also shares strong sequence homology to the mammalian tachykinin receptors (NK1R, NK2R, and NK3R), whose endogenous ligands are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), respectively. The tachykinins function as excitatory transmitters on neurons and cells in the gastrointestinal tract.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  18 GIWVVSVLLAVPEAVFSEVARISSLDNSSFTACIPYPQTDelHPKIHSVLIFLVYFLIPLAIISIYYYHIAktLIKSAHN 97
Cdd:cd15392   122 VIWIFALATALPIAITSRLFEDSNASCGQYICTESWPSDT--NRYIYSLVLMILQYFVPLAVLVFTYTRIG--IVVWAKR 197

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1024249356  98 LPGEYNEHTKKQM-ETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNeiDPSLGHM-IVTLVARVLSFGNSCVNPFA 175
Cdd:cd15392   198 TPGEAENNRDQRMaESKRKLVKMMITVVAIFALCWLPLNILNLVGDHDES--IYSWPYIpYLWLAAHWLAMSHCCYNPFI 275

                         170
                  ....*....|..
gi 1024249356 176 LYLLSESFRRHF 187
Cdd:cd15392   276 YCWMNAKFRNGF 287