Structural Insights into the Process of GPCR-G Protein Complex Formation

Xiangyu Liu; Xinyu Xu; Daniel Hilger; Philipp Aschauer; Johanna K S Tiemann; Yang Du; Hongtao Liu; Kunio Hirata; Xiaoou Sun; Ramon Guixà-González; Jesper M Mathiesen; Peter W Hildebrand; Brian K Kobilka

doi:10.1016/j.cell.2019.04.021

Structural Insights into the Process of GPCR-G Protein Complex Formation

Cell. 2019 May 16;177(5):1243-1251.e12. doi: 10.1016/j.cell.2019.04.021. Epub 2019 May 9.

Authors

Affiliations

¹ Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
² Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
³ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Institute for Molecular Bioscience, University of Graz, Humboldtstrasse 50/3, 8010 Graz, Austria.
⁵ Institute of Medical Physics and Biophysics, Charité Medical University Berlin, Berlin 10117, Germany; Institute of Medical Physics and Biophysics, Faculty of Medicine, University Leipzig, Leipzig 04107, Germany.
⁶ Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, 1-1-1 Kouto Sayo-cho Sayo-gun, Hyogo 679-5148, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
⁷ Institute of Medical Physics and Biophysics, Charité Medical University Berlin, Berlin 10117, Germany.
⁸ Department of Drug Design and Pharmacology, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
⁹ Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].

Abstract

The crystal structure of the β2-adrenergic receptor (β2AR) bound to the G protein adenylyl cyclase stimulatory G protein (Gs) captured the complex in a nucleotide-free state (β2AR-Gs^empty). Unfortunately, the β2AR-Gs^empty complex does not provide a clear explanation for G protein coupling specificity. Evidence from several sources suggests the existence of a transient complex between the β2AR and GDP-bound Gs protein (β2AR-Gs^GDP) that may represent an intermediate on the way to the formation of β2AR-Gs^empty and may contribute to coupling specificity. Here we present a structure of the β2AR in complex with the carboxyl terminal 14 amino acids from Gαs along with the structure of the GDP-bound Gs heterotrimer. These structures provide evidence for an alternate interaction between the β2AR and Gs that may represent an intermediate that contributes to Gs coupling specificity.

Keywords: G protein; G protein-coupled receptor; coupling specificity; intermediate state; protein engineering.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenylyl Cyclases / chemistry*
GTP-Binding Protein alpha Subunits, Gs / chemistry*
Humans
Models, Molecular*
Receptors, Adrenergic, beta-2 / chemistry*
Structure-Activity Relationship

Substances

Receptors, Adrenergic, beta-2
GTP-Binding Protein alpha Subunits, Gs
Adenylyl Cyclases

Grants and funding

R01 GM083118/GM/NIGMS NIH HHS/United States