title: Crystal structure of the β2 adrenergic receptor-Gs protein complex.
abstract: 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 β(2) adrenergic receptor (β(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 β(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the β(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β(2)AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Søren G F
authors.initials: SG
authors.lastname: Rasmussen
authors.forename: Brian T
authors.initials: BT
authors.lastname: DeVree
authors.forename: Yaozhong
authors.initials: Y
authors.lastname: Zou
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Chung
authors.forename: Tong Sun
authors.initials: TS
authors.lastname: Kobilka
authors.forename: Foon Sun
authors.initials: FS
authors.lastname: Thian
authors.forename: Pil Seok
authors.initials: PS
authors.lastname: Chae
authors.forename: Els
authors.initials: E
authors.lastname: Pardon
authors.forename: Diane
authors.initials: D
authors.lastname: Calinski
authors.forename: Jesper M
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Syed T A
authors.initials: ST
authors.lastname: Shah
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Martin
authors.initials: M
authors.lastname: Caffrey
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D003460:Crystallization; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D046912:Multiprotein Complexes; D018343:Receptors, Adrenergic, beta-2; D019205:GTP-Binding Protein alpha Subunits, Gs