Structural basis for regulation of a human GPCR by membrane lipids investigated by NMR spectroscopy

Abstract

G protein-coupled receptors (GPCRs) are sensory proteins that comprise the largest class of “druggable” targets. Earlier NMR studies demonstrated that GPCRs exist in a function-related equilibrium of simultaneously populated conformers, the relative populations of which are determined by the efficacy of bound drugs. We now present NMR data that show membrane phospholipids and sterols also control this equilibrium with a magnitude comparable to or greater than the influence of drug efficacy. Using NMR spectroscopy in aqueous solutions, we investigated the structural basis for the regulation of GPCR activity by phospholipids in nanodiscs containing the human A2A adenosine receptor (A2AAR), a representative class A GPCR.