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.
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 Eric, Yang Dehua, Zhao Lihua, Wang Ming-Wei
human, molecular biophysics, structural biology