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

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

doi:10.7554/elife.68719

Abstract

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.

Highlights

IntroductionGlucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid peptide hormone that plays crucial role in glucose regulation and fatty acid metabolism
The pleiotropic functions of GIP is mediated by its cognate receptor (GIPR), a member of class B1 G protein-coupled receptors (GPCRs) that include glucagon receptor (GCGR) and glucagon-like peptide-1 (GLP-1R)
To solve the GIP1-42–GIPR–Gs structure, we further introduced one mutation (T345F) to stabilize the assembly of complex (Fig. S1C, D)

Summary

Introduction

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid peptide hormone that plays crucial role in glucose regulation and fatty acid metabolism. In response to food intake, GIP is secreted by intestinal K cells to enhance insulin secretion and peripheral fatty acid uptake (1), as well as a number of neuronal effects (2). The pleiotropic functions of GIP is mediated by its cognate receptor (GIPR), a member of class B1 G protein-coupled receptors (GPCRs) that include glucagon receptor (GCGR) and glucagon-like peptide-1 (GLP-1R). GIPR, together with GCGR and GLP-1R, form the central endocrine network in regulating insulin sensitivity and energy homeostasis, and they are validated drug targets (3-5). A number of GLP-1R selective ligands have been developed successfully to treat type 2 diabetes and obesity.

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Conclusion