Format

Send to

Choose Destination
Nature. 2017 Jun 8;546(7657):259-264. doi: 10.1038/nature22363. Epub 2017 May 17.

Structure of the full-length glucagon class B G-protein-coupled receptor.

Zhang H1,2, Qiao A1,2, Yang D1,3, Yang L4, Dai A1,3, de Graaf C5, Reedtz-Runge S6, Dharmarajan V7, Zhang H1,2, Han GW8, Grant TD9, Sierra RG10, Weierstall U11, Nelson G11, Liu W12, Wu Y1,2,13, Ma L1, Cai X1,3, Lin G1,2,3,13, Wu X14, Geng Z15, Dong Y15, Song G16, Griffin PR7, Lau J6, Cherezov V8, Yang H17, Hanson MA18, Stevens RC13,16, Zhao Q1,2,19,20, Jiang H1,17,19, Wang MW1,3,13,21, Wu B1,2,13,20.

Author information

1
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
2
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
3
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China.
4
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
5
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands.
6
Novo Nordisk A/S, Novo Nordisk Park, Måløv 2760, Denmark.
7
Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.
8
Department of Chemistry, Bridge Institute, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, California 90089, USA.
9
Hauptman-Woodward Institute, SUNY at Buffalo, 700 Ellicott Street, Buffalo, New York 14203, USA.
10
Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
11
Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
12
Biodesign Center for Applied Structural Discovery, Biodesign Institute, School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, USA.
13
School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China.
14
Novo Nordisk Research Centre China, No. 20 Life Science Park Road, Changping District, Beijing 102206, China.
15
Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
16
iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China.
17
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
18
GPCR Consortium, San Marcos, California 92078, USA.
19
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
20
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
21
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.

Abstract

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.

PMID:
28514451
PMCID:
PMC5492955
DOI:
10.1038/nature22363
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center