Structural basis of G_s and G_i recognition by the human glucagon receptor

Anna Qiao^{1

2

3}, Shuo Han^{1

2}, Xinmei Li^{3

4}, Zhixin Li⁵, Peishen Zhao⁶, Antao Dai^{1

7}, Rulve Chang⁵, Linhua Tai^{3

4}, Qiuxiang Tan^{1

2}, Xiaojing Chu^{1

2}, Limin Ma^{1

2}, Thor Seneca Thorsen⁸, Steffen Reedtz-Runge⁸, Dehua Yang^{1

7}, Ming-Wei Wang^{1

3

5

7

9}, Patrick M Sexton^{5

6}, Denise Wootten^{10

6}, Fei Sun^{11

4

12}, Qiang Zhao^{13

3

14}, Beili Wu^{15

3

9

14}

Affiliations

¹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ 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.
⁵ School of Pharmacy, Fudan University, Shanghai 201203, China.
⁶ Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁷ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Novo Nordisk A/S, Måløv 2760, Denmark.
⁹ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹⁰ School of Pharmacy, Fudan University, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing 100049, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹² Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
¹³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹⁴ CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
¹⁵ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.

PMID: 32193322
DOI: 10.1126/science.aaz5346

Structural basis of G_s and G_i recognition by the human glucagon receptor

Anna Qiao et al. Science. 2020.

. 2020 Mar 20;367(6484):1346-1352.

doi: 10.1126/science.aaz5346.

Authors

Affiliations

¹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ 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.
⁵ School of Pharmacy, Fudan University, Shanghai 201203, China.
⁶ Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁷ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Novo Nordisk A/S, Måløv 2760, Denmark.
⁹ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹⁰ School of Pharmacy, Fudan University, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing 100049, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹² Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
¹³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.
¹⁴ CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
¹⁵ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. denise.wootten@monash.edu feisun@ibp.ac.cn zhaoq@simm.ac.cn beiliwu@simm.ac.cn.

PMID: 32193322
DOI: 10.1126/science.aaz5346

Abstract

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G_s class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, G_s or G_i1 These two structures adopt a similar open binding cavity to accommodate G_s and G_i1 The G_s binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect G_i more than G_s binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.

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Structural basis of G_s and G_i recognition by the human glucagon receptor

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Structural basis of G_s and G_i recognition by the human glucagon receptor

Authors

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Abstract

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