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Nature. 2018 Jan 3;553(7686):106-110. doi: 10.1038/nature25153.

Structure of the glucagon receptor in complex with a glucagon analogue.

Zhang H1,2,3, Qiao A1,2,3, Yang L4, Van Eps N5, Frederiksen KS6, Yang D1,7, Dai A1,7, Cai X1,7, Zhang H1,3, Yi C1, Cao C3,8, He L8, Yang H9, Lau J6, Ernst OP5,10, Hanson MA11, Stevens RC12,13, Wang MW1,3,7,13,14, Reedtz-Runge S6, Jiang H1,2,15, Zhao Q1,2,3,16, Wu B1,3,13,16.

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
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
3
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
4
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
5
Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6
Novo Nordisk A/S, Novo Nordisk Park, Måløv 2760, Denmark.
7
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China.
8
National Laboratory of Biomacromolecules, National Center of Protein Science - Beijing, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
9
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
10
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
11
GPCR Consortium, San Marcos, California 92078, USA.
12
iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China.
13
School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China.
14
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
15
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
16
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.

Abstract

Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases. Previous work has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 Å-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.

PMID:
29300013
DOI:
10.1038/nature25153
[Indexed for MEDLINE]

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