Emerging opportunities for allosteric modulation of G-protein coupled receptors

摘要: Their ubiquitous nature, wide cellular distribution and versatile molecular recognition signalling help make G-protein binding receptors (GPCRs) the most important class of membrane proteins in clinical medicine, accounting for ∼40% all current therapeutics. A large percentage drugs target endogenous ligand (orthosteric) site, which are structurally evolutionarily conserved, particularly among members same GPCR subfamily. With recent advances X-ray crystallography, new opportunities developing novel subtype selective have emerged. Given increasing that extracellular surface conformation changes response to binding, it is likely GPCRs possess an allosteric site(s) capable regulating signalling. Allosteric sites less conserved than their corresponding orthosteric site thus provide development more drugs. Constitutive oligomerisation (dimerisation) identified many investigated, adds another dimension structural functional complexity GPCRs. In this review, we compare 60 crystal structures nine subtypes (rhodopsin, s₂-AR, s₁-AR, A(2a)-AR, CXCR4, D₃R, H₁R, M₂R, M₃R) across four subfamilies Class GPCRs, discuss mechanisms involved receptor activation potential highly variable these This analysis has a salt bridge (ESB-2) might be exploited design modulators.