The research team of Zhenhua Shao, a research fellow at the State Key Laboratory of Biotherapy and Cancer Center of West China Hospital, SCU, has recently published in Nature Communications a research paper entitled “Structure of the Human Gonadotropin-releasing Hormone Receptor GnRH1R Reveals an Unusual Ligand Binding Mode”. SCU’s State Key Laboratory of Biotherapy and Cancer Center is the first work unit of this research, and the first authors are Wei Yan, an associate research fellow and Lin Cheng, a postdoctoral fellow. Prof. Shengyong Yang and Prof. Liang Ma have taken part in the research. The hypothalamus secretes gonadotropin-releasing hormone GnRH, which acts on GnRH receptor (gnrh1r) in pituitary gonadotropic cells, and regulates the release of luteinizing hormone and follicle stimulating hormone, controlling gonadal development and secretion of sex hormone. “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.” (Abstract)
a View from within the plane of membrane. GnRH1R is shown in sky blue cartoon representation. The N terminus is displayed as sand cartoon. The antagonist elagolix is shown as sphere with cyan carbons. b Receptor recognition drug pocket.cThe N-terminus of the receptor and the ligand share a positive pocket.
Elagolix (trade name Orilissa), the first oral non peptide small molecule antagonist of GnRH1R, is used to treat diseases such as EMS. The team reports for the first time the crystal structure of human GnRH1R in complex with the antagonist drug elagolix. Compared with other GPCRs, the GnRH1R structure contains an unusual orthosteric site in which the antagonist and the N terminus of the protein could co-occupy an enlarged binding pocket. The research results havelaid a solid structural foundation for drug research and development.
Article link: https://www.nature.com/articles/s41467-020-19109-w
