Recently, the research team led by Prof. Shao Zhenhua from the State Key Laboratory of Biotherapy, West China Hospital (WCH) published a research paper entitled Structure of the Human Gonadotropin-releasing Hormone Receptor GnRH1R Reveals an unusual Ligand Binding Mode in the international journal--Nature Communications (IF: 12.1), revealing a new mechanism of how GPCR recognizes drugs.

The research was mainly completed by Prof. Shao Zhenhua’s research team. The State Key Laboratory of Biotherapy and Nephrology Research institute of WCH are the first corresponding address, while associate professor Yan Wei and postdoc Cheng Lin are the co-first authors. Prof. Yang Shengyong and Prof. Ma Liang of WCH, etc, participated in the research.

Hypothalamus secretes gonadotropin-releasing hormone (GnRH) acts on the GnRH receptor (GnRH1R) in the pituitary gonadotropin cells, so as to regulate the release of luteinizing hormone and follicle-stimulating hormone, and control the gonadal development and sex hormone secretion, etc. GnRH1R belongs to the G protein coupled receptor (GPCR) family. Studies have shown that GnRH1R is a direct target for the treatment of uterine leiomyoma, endometriosis (EMs), prostate cancer and other related diseases.

Elagolix (Trade name: Orilissa), the first oral non-peptide small molecule antagonist of GnRH1R, is used to treat diseases such as EMs. The team reported for the first time the 2.8 Å crystal structure of the human GnRH1R receptor and the drug elagolix (approved by FDA in 2018) compound. Furthermore, the GPCR signal transduction experiment, molecular docking, and molecular dynamics simulation, etc, were employed to reveal the molecular mechanism of GnRH1R identifying antagonist ligands, thus providing a detailed structural basis for drug discovery and development.

Linkage to the original article: https://www.nature.com/articles/S41467-020-19109-w