Crystal structure of the β2 adrenergic receptor–Gs protein complex

Søren G. F. Rasmussen, Brian T. DeVree, Yaozhong Zou, Andrew C. Kruse, Ka Young Chung, Tong Sun Kobilka, Foon Sun Thian, Pil Seok Chae, Els Pardon, Diane Calinski, Jesper M. Mathiesen, Syed T. A. Shah, Joseph A. Lyons, Martin Caffrey, Samuel H. Gellman, Jan Steyaert, Georgios Skiniotis, William I. Weis, Roger K. Sunahara () and Brian K. Kobilka ()
Additional contact information
Søren G. F. Rasmussen: Stanford University School of Medicine
Brian T. DeVree: University of Michigan Medical School
Yaozhong Zou: Stanford University School of Medicine
Andrew C. Kruse: Stanford University School of Medicine
Ka Young Chung: Stanford University School of Medicine
Tong Sun Kobilka: Stanford University School of Medicine
Foon Sun Thian: Stanford University School of Medicine
Pil Seok Chae: University of Wisconsin
Els Pardon: Vlaams Instituut voor Biotechnologie (VIB), Vrije Universiteit Brussel
Diane Calinski: University of Michigan Medical School
Jesper M. Mathiesen: Stanford University School of Medicine
Syed T. A. Shah: Membrane Structural and Functional Biology Group, Schools of Medicine and Biochemistry & Immunology, Trinity College
Joseph A. Lyons: Membrane Structural and Functional Biology Group, Schools of Medicine and Biochemistry & Immunology, Trinity College
Martin Caffrey: Membrane Structural and Functional Biology Group, Schools of Medicine and Biochemistry & Immunology, Trinity College
Samuel H. Gellman: University of Wisconsin
Jan Steyaert: Vlaams Instituut voor Biotechnologie (VIB), Vrije Universiteit Brussel
Georgios Skiniotis: University of Michigan
William I. Weis: Stanford University School of Medicine
Roger K. Sunahara: University of Michigan Medical School
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2011, vol. 477, issue 7366, 549-555

Abstract: 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 β2 adrenergic receptor (β2AR) 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 β2AR and nucleotide-free Gs heterotrimer. The principal interactions between the β2AR 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 β2AR 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.

Date: 2011
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DOI: 10.1038/nature10361

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