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

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

Author information

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: liu_xy@mail.tsinghua.edu.cn.
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: kobilka@stanford.edu.

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-Gsempty). Unfortunately, the β2AR-Gsempty 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-GsGDP) that may represent an intermediate on the way to the formation of β2AR-Gsempty 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

PMID:
31080070
DOI:
10.1016/j.cell.2019.04.021

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