Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

Wei Yan, Lin Cheng, Wei Wang, Chao Wu, Xin Yang, Xiaozhe Du, Liang Ma, Shiqian Qi, Yuquan Wei, Zhiliang Lu, Shengyong Yang and Zhenhua Shao ()
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Wei Yan: West China Hospital, Sichuan University
Lin Cheng: West China Hospital, Sichuan University
Wei Wang: West China Hospital, Sichuan University
Chao Wu: West China Hospital, Sichuan University
Xin Yang: West China Hospital, Sichuan University
Xiaozhe Du: Xi’an Jiaotong-Liverpool University
Liang Ma: West China Hospital, Sichuan University
Shiqian Qi: West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy
Yuquan Wei: West China Hospital, Sichuan University
Zhiliang Lu: Xi’an Jiaotong-Liverpool University
Shengyong Yang: West China Hospital, Sichuan University
Zhenhua Shao: West China Hospital, Sichuan University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.

Date: 2020
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DOI: 10.1038/s41467-020-19109-w

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