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

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-...

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Bibliographic Details
Published in:eLife 2021-07, Vol.10
Main Authors: Zhao, Fenghui, Zhang, Chao, Zhou, Qingtong, Hang, Kaini, Zou, Xinyu, Chen, Yan, Wu, Fan, Rao, Qidi, Dai, Antao, Yin, Wanchao, Shen, Dan-Dan, Zhang, Yan, Xia, Tian, Stevens, Raymond C, Xu, H Eric, Yang, Dehua, Zhao, Lihua, Wang, Ming-Wei
Format: Article
Language:English
Subjects:
Amino acids
Animals
C-Terminus
Cell Line
Chromatography
cryo-electron microscopy
Cryoelectron Microscopy
Data collection
Fatty acids
G protein-coupled receptor
Gastric Inhibitory Polypeptide - chemistry
Gastric Inhibitory Polypeptide - metabolism
GIP protein
Glucagon
Glucose
glucose-dependent insulinotropic polypeptide receptor
Humans
ligand recognition
Ligands
Lipids
Molecular Dynamics Simulation
Mutation
Polypeptides
Protein Conformation
Protein Conformation, alpha-Helical
Protein Domains
Proteins
Receptors, Gastrointestinal Hormone - chemistry
Receptors, Gastrointestinal Hormone - metabolism
Structural Biology and Molecular Biophysics
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Summary: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 G 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.68719