Structure of the human glucagon class B G-protein-coupled receptor

Fai Yiu Siu, Min He, Chris de Graaf, Gye Won Han, Dehua Yang, Zhiyun Zhang, Caihong Zhou, Qingping Xu, Daniel Wacker, Jeremiah S. Joseph, Wei Liu, Jesper Lau, Vadim Cherezov, Vsevolod Katritch, Ming-Wei Wang () and Raymond C. Stevens ()
Additional contact information
Fai Yiu Siu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Min He: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China
Chris de Graaf: Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University of Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Gye Won Han: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Dehua Yang: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China
Zhiyun Zhang: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China
Caihong Zhou: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China
Qingping Xu: The Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA
Daniel Wacker: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Jeremiah S. Joseph: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Wei Liu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Jesper Lau: Protein & Peptide Chemistry, Novo Nordisk, Novo Nordisk Park, 2760 Malov, Denmark
Vadim Cherezov: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Vsevolod Katritch: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Ming-Wei Wang: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China
Raymond C. Stevens: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Nature, 2013, vol. 499, issue 7459, 444-449

Abstract: Abstract Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 Å resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a ‘stalk’ region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (∼12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon’s amino terminus into the seven transmembrane domain.

Date: 2013
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DOI: 10.1038/nature12393

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