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

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.

A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2

“…1c). Its overall structure is similar to other class B1 GPCRs–G s complexes such as GLP-1–GLP-1R–G s (PDB code: 6×18) 24 , GIP–GIPR–G s (PDB code: 7DTY) 25 , TIP39–PTH2R–G s (PDB code: 7F16) 26 and UCN1–CRF1R–G s (PDB code: 6PB0) 27 with root mean square deviation (RMSD) values of 1.40, 0.99, 1.39, and 0.96 Å for the whole complex, respectively. Meanwhile, the structure of PACAP27-bound VIP2R displays a high degree of similarity compared to both PACAP27-bound VIP1R (PDB code: 6VN7) 13 and PAC1R bound by PACAP38 (PDB code: 6P9Y) 16 and maxadilan (PDB code: 6M1H) 14 , with Cα RMSD of 0.70, 0.96 and 1.04 Å, respectively.…”

“…In the case of parathyroid hormone (PTH) receptors whose ECL1s are unstructured, PTH1R 21 and PTH2R 26 rotate their N-terminal α-helices to stand upwards in line with the bound peptides, thereby providing additional contacts with the latter. Different from the ECL1-top conformation seen in PAC1R or the ECL2-top position observed in PTH1R/PTH2R, the N-terminal α-helices of glucagon receptor family members (GLP-1R 24 , GIPR 25 and sCTR 28 shown in Fig. 4c) locate in the middle of ECL1 and ECL2, and stabilize the peptide C terminus with the assistance of ECL1.…”