Cited by 3,009Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology Research

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Crystal structure of the β2 adrenergic receptor–Gs protein complex

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Rasmussen, Søren G. F., DeVree, Brian T., Zou, Yaozhong, Kruse, Andrew C., Chung, Ka Young, Kobilka, Tong Sun, Thian, Foon Sun, Chae, Pil Seok, Pardon, Els, Calinski, Diane, Mathiesen, Jesper M., Shah, Syed T. A., Lyons, Joseph A., Caffrey, Martin, Gellman, Samuel H., Steyaert, Jan, Skiniotis, Georgios, Weis, William I., Sunahara, Roger K., Kobilka, Brian K.·2011·Nature

DOI 10.1038/nature10361PMC PMC3184188

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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.

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Chung, K. Y. et al. β2 adrenergic receptor-induced conformational changes in the heterotrimeric G protein Gs. Nature 10.1038/nature10488 (this issue) · DOI

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Authors: Rasmussen, S. G. F., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., Mathiesen, J. M., Shah, S. T. A., Lyons, J. A., Caffrey, M., Gellman, S. H., Steyaert, J., Skiniotis, G., Weis, W. I., Sunahara, R. K., & Kobilka, B. K.
Affiliations: University of Copenhagen (DK)
University of Michigan (US)
Stanford Medicine (US)
University of Wisconsin–Madison (US)
Vrije Universiteit Brussel (BE)
Trinity College Dublin (IE)
Corresponding author: Sunahara, Roger K.
Kobilka, Brian K.
ORCID: Rasmussen, Søren G. F.
DeVree, Brian T.
Kruse, Andrew C.
Chung, Ka Young
Chae, Pil Seok
Pardon, Els
Calinski, Diane
Mathiesen, Jesper M.
Shah, Syed T. A.
Lyons, Joseph A.
Caffrey, Martin
Gellman, Samuel H.
Steyaert, Jan
Skiniotis, Georgios
Weis, William I.
Sunahara, Roger K.
Kobilka, Brian K.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-07-19
Volume: 477
Issue: 7366
Pages: 549-555
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10361
PMC: PMC3184188
OpenAlex: W2167857702
Cited by: 3,009
References: 48
Citations by year: 2026: 93 · 2025: 145 · 2024: 159 · 2023: 147 · 2022: 161 · 2021: 168 · 2020: 177 · 2019: 195 · 2018: 212 · 2017: 234 · 2016: 238 · 2015: 258 · 2014: 255 · 2013: 301 · 2012: 202
FWCI: 107.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Scopus (Elsevier) (submittedVersion)
VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders: Sundhed og Sygdom, Det Frie Forskningsråd
Science Foundation Ireland (07/IN.1/B1836)
Fonds Wetenschappelijk Onderzoek
Lundbeckfonden (R19-2008-2113, R37-2009-3457)
Danmarks Frie Forskningsfond
Vlaamse regering
H. Lundbeck A/S
National Institutes of Health (GM56169, GM75915)
National Institute of General Medical Sciences (R01GM075915, U54GM094599, GM083118, GM 56169, P01GM075913, P01 GM75913, R01GM083118, P50GM073210, T32GM008270, GM75915, R01GM056169, R01GM068603)
National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, P60 DK 20572)
National Institute of Neurological Disorders and Stroke (NS-028471, R01NS028471, R37NS028471)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: beta2-adrenergic receptor, Gs protein, G protein-coupled receptors, G protein-coupled receptor signaling, adenylate cyclase, GPCR crystal structures, protein dynamics
MeSH terms: Animals, Cattle, Crystallization, Enzyme Activation, Models, Molecular, Protein Binding, Receptors, Adrenergic, beta-2, Crystallography, X-Ray, GTP-Binding Protein alpha Subunits, Gs, Catalytic Domain, Multiprotein Complexes, Rats, Adrenergic beta-2 Receptor Agonists

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Crystal structure of the β2 adrenergic receptor–Gs protein complex

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