Extending the Structural View of Class B GPCRs

Chris de Graaf; Gaojie Song; Can Cao; Qiang Zhao; Ming-Wei Wang; Beili Wu; Raymond C Stevens

doi:10.1016/j.tibs.2017.10.003

Extending the Structural View of Class B GPCRs

Trends Biochem Sci. 2017 Dec;42(12):946-960. doi: 10.1016/j.tibs.2017.10.003. Epub 2017 Nov 11.

Authors

Chris de Graaf¹, Gaojie Song², Can Cao³, Qiang Zhao⁴, Ming-Wei Wang⁵, Beili Wu⁶, Raymond C Stevens⁷

Affiliations

¹ 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; These authors contributed equally.
² iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China; These authors contributed equally.
³ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; These authors contributed equally.
⁴ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China; CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
⁵ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; National Center for Drug Screening, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
⁶ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China.
⁷ iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, 3430 South Vermont Avenue, Los Angeles, CA 90089, USA. Electronic address: stevens@shanghaitech.edu.cn.

PMID: 29132948
DOI: 10.1016/j.tibs.2017.10.003

Abstract

The secretin-like class B family of G protein-coupled receptors (GPCRs) are key players in hormonal homeostasis. Recent structures of various receptors in complex with a variety of orthosteric and allosteric ligands provide fundamental new insights into the function and mechanism of class B GPCRs, including: (i) ligand-induced changes in the relative orientation of the extracellular and transmembrane receptor domains; (ii) intramolecular interaction networks that stabilize conformational changes to accommodate intracellular G protein binding; and (iii) allosteric modulation of receptor activation. This review provides a comprehensive analysis of the structural, biochemical, and pharmacological data on class B GPCRs for understanding ligand-receptor interaction and modulation mechanisms and assessing the potential implications for drug discovery for the secretin-like GPCR family.

Keywords: calcitonin receptor; class B G protein-coupled receptor; glucagon receptor; glucagon-like peptide-1 receptor; structural biology; structure–function relationship.

Publication types

Review

MeSH terms

Humans
Ligands
Protein Conformation
Receptors, G-Protein-Coupled / chemistry*
Receptors, G-Protein-Coupled / metabolism

Substances

Ligands
Receptors, G-Protein-Coupled