PT  - JOURNAL ARTICLE
AU  - Fenghui Zhao
AU  - Chao Zhang
AU  - Qingtong Zhou
AU  - Kaini Hang
AU  - Xinyu Zou
AU  - Yan Chen
AU  - Fan Wu
AU  - Qidi Rao
AU  - Antao Dai
AU  - Wanchao Yin
AU  - Dan-Dan Shen
AU  - Yan Zhang
AU  - Tian Xia
AU  - Raymond C. Stevens
AU  - H. Eric Xu
AU  - Dehua Yang
AU  - Lihua Zhao
AU  - Ming-Wei Wang
TI  - Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor
AID  - 10.1101/2021.03.18.436101
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.18.436101
4099  - http://biorxiv.org/content/early/2021/03/19/2021.03.18.436101.short
4100  - http://biorxiv.org/content/early/2021/03/19/2021.03.18.436101.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.