Crystal structure of the β2 adrenergic receptor-Gs protein complex

TY - JOUR

T1 - Crystal structure of the β2 adrenergic receptor-Gs protein complex

AU - Rasmussen, Søren Gøgsig Faarup

AU - DeVree, Brian T

AU - Zou, Yaozhong

AU - Kruse, Andrew C

AU - Chung, Ka Young

AU - Kobilka, Tong Sun

AU - Thian, Foon Sun

AU - Chae, Pil Seok

AU - Pardon, Els

AU - Calinski, Diane

AU - Mathiesen, Jesper M

AU - Shah, Syed T A

AU - Lyons, Joseph A

AU - Caffrey, Martin

AU - Gellman, Samuel H

AU - Steyaert, Jan

AU - Skiniotis, Georgios

AU - Weis, William I

AU - Sunahara, Roger K

AU - Kobilka, Brian K

N1 - © 2011 Macmillan Publishers Limited. All rights reserved

PY - 2011/9/29

Y1 - 2011/9/29

N2 - 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.

AB - 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.

KW - Adrenergic beta-2 Receptor Agonists

KW - Animals

KW - Catalytic Domain

KW - Cattle

KW - Crystallization

KW - Crystallography, X-Ray

KW - Enzyme Activation

KW - GTP-Binding Protein alpha Subunits, Gs

KW - Models, Molecular

KW - Multiprotein Complexes

KW - Protein Binding

KW - Rats

KW - Receptors, Adrenergic, beta-2

U2 - 10.1038/nature10361

DO - 10.1038/nature10361

M3 - Journal article

C2 - 21772288

SN - 0028-0836

VL - 477

SP - 549

EP - 555

JO - Nature

JF - Nature

IS - 7366

ER -