Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor
Fenghui Zhao,
Chao Zhang,
Qingtong Zhou,
Kaini Hang,
Xinyu Zou,
Yan Chen,
Fan Wu,
Qidi Rao,
Antao Dai,
Wanchao Yin,
Dan-Dan Shen,
Yan Zhang,
Tian Xia,
Raymond C Stevens,
H Eric Xu,
Dehua Yang,
Lihua Zhao,
Ming-Wei Wang
Affiliations
Fenghui Zhao
School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Chao Zhang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Kaini Hang
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Xinyu Zou
School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China
Yan Chen
School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Fan Wu
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Qidi Rao
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Antao Dai
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Wanchao Yin
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Dan-Dan Shen
Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Yan Zhang
Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Tian Xia
School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China
Raymond C Stevens
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
H Eric Xu
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Lihua Zhao
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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.
