Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Fenghui Zhao; Chao Zhang; Qingtong Zhou; Kaini Hang; Xinyu Zou; Yan Chen; Fan Wu; Qidi Rao; Antao Dai; Wanchao Yin; Dan-Dan Shen; Yan Zhang; Tian Xia; Raymond C Stevens; H Eric Xu; Dehua Yang; Lihua Zhao; Ming-Wei Wang

doi:10.7554/eLife.68719

eLife (Jul 2021)

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Fenghui Zhao,
Chao Zhang,
Qingtong Zhou,
Kaini Hang,
Xinyu Zou,
Yan Chen,
Fan Wu,
Qidi Rao,
Antao Dai,
Wanchao Yin,
Dan-Dan Shen,
Yan Zhang,
Tian Xia,
Raymond C Stevens,
H Eric Xu,
Dehua Yang,
Lihua Zhao,
Ming-Wei Wang

Affiliations

Fenghui Zhao: School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Chao Zhang: School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Qingtong Zhou: ORCiD; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Kaini Hang: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Xinyu Zou: School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China
Yan Chen: School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Fan Wu: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Qidi Rao: School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Antao Dai: The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Wanchao Yin: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Dan-Dan Shen: Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Yan Zhang: Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Tian Xia: School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China
Raymond C Stevens: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
H Eric Xu: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Dehua Yang: ORCiD; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Lihua Zhao: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Ming-Wei Wang: ORCiD; School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

DOI: https://doi.org/10.7554/eLife.68719
Journal volume & issue: Vol. 10

Abstract

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Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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