Ligand-binding SRPBCC domain of Micromonospora echinospora CalC and related proteins
This subfamily includes Micromonospora echinospora CalC (MeCalC) and related proteins. These proteins belong to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins which bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. MeCalC confers resistance to the enediyne, calicheamicin gamma 1 (CLM). Enediyne antibiotics are antitumor agents. Enediynes have an in vitro and in vivo role as DNA damaging agents; they consist of a DNA recognition unit (e.g., aryltetrasaccharide of CLM), an activating component (e.g., methyl trisulfide of CLM), which promotes cycloaromatization, and the enediyne warhead which cycloaromatizes to a reactive diradical species, resulting in oxidative strand cleavage of the targeted DNA sequence. MeCalC confers resistance to CLM by a self sacrificing mechanism: the transient enediyne diradical species abstracts a CalC Gly Calpha-hydrogen, thereby quenching the reactive enediyne moiety, and generating a CalC Gly Calpha radical. This radical then reacts with oxygen, leading to oxidative site-specific proteolysis of CalC. This antibiotic-induced proteolysis of CalC results in inactivation of both CalC and the highly reactive diradical species. CalC has also been shown to inactivate two other enediynes, shishijimicin and namenamicin. The crucial Gly of the MeCalC CLM resistance mechanism is contained in a loop (L1) which is displaced when CLM is bound, this Gly is not conserved in this subgroup.
Comment:Calicheamicin gamma-1 (CLM), is a core bicyclo (7.3.1) tridecadiynene moiety (enediyne warhead) attached to an aryltetrasaccharide chain.
Structure:2GKC_A; Micromonospora echinospora CalC binds CLM, contacts at 4A.
Comment:CLM is bound with its DNA-recognition unit buried, its trisulfide trigger solvent exposed (faciltiating activation), and its enediyne warhead positioned to initiate the CalC self sacrifice process.
Jiyao W et al.(2023). "The conserved domain database in 2023.",