Crystal structure of the beta(2) adrenergic receptor-Gs protein complex

G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The beta(2) adrenergic receptor (beta(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric beta(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the beta(2)AR and Gs involve the amino-and carboxy-terminal a-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the beta(2)AR include a 14 angstrom outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an alpha-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the alpha-helical domain of G alpha s relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.We acknowledge support from National Institutes of Health Grants NS028471 (B.K.K.) and GM083118 (B.K.K. and R.K.S.),GM56169 (W.I.W.), P01GM75913 (S.H.G), T32-GM008270 and P60DK-20572 (R.K.S.), GM75915, P50GM073210 and U54GM094599 (M.C.), Science Foundation Ireland (07/IN.1/B1836) and FP7 COST Action CM0902 (M.C.),the Mathers Foundation (B.K.K. and W.I.W.), the Lundbeck Foundation (Junior Group Leader Fellowship, S.G.F.R.), the University of Michigan Biomedical Sciences Scholars Program (R.K.S.), the Fund for Scientific Research of Flanders (FWO-Vlaanderen) and the Institute for theencouragement of Scientific Research and Innovation of Brussels (ISRIB) (E.P. and J.S.), The Danish Council for Independent Research, Medical Sciences (J.M.M.). We thank D.Grayson and A. Coughlan for help with lipid synthesis