人源促性腺激素释放激素受体GnRH1R识别负向别构调节剂的分子机理

促性腺激素释放激素GnRH和促性腺激素释放激素受体GnRH1R作为下丘脑-垂体-性腺轴中重要一环，调控人体生殖系统的生长发育，已成为子宫内膜异位症，子宫纤维瘤、前列腺癌等疾病的重要治疗靶点。目前市场上GnRH1R靶点药物都存在一定副作用，主要为：潮热、关节疼痛及骨质疏松。2020年我们发表在Nature Communications 上的GnRH1R与拮抗剂elagolix的结构发现了一个可能的GnRH1R负向别构调节剂结合位点。GnRH1R负向别构调节剂能抑制或阻断GnRH1R的信号途径，是GnRH1R靶点潜在的药物，具有一定的社会经济价值，其分子机制的缺失是当前的负向别构调节剂药物开发的主要瓶颈。因此，我们拟通过晶体学方法解析GnRH1R与负向别构调节剂furan-1、HMA的高分辨率晶体结构，并结合信号转导实验、分子动力学模拟，阐明负向别构调节剂调节GnRH1R功能的分子机制。

Gonadotrophin releasing hormone (GnRH) and gonadotrophin releasing hormone receptor (GnRH1R), as an important parts of hypothalamus-pituitary-gonadal (HPG) axis, regulate the growth and development of human reproductive system, and have become important therapeutic targets for endometriosis, uterine fibroma, prostate cancer and other diseases. At present, the drugs target GnRH1R on the market have certain side effects, mainly as hot flashes, arthralgia and osteoporosis. A possible negative allosteric modulator (NAM) binding site of GnRH1R was been found by analyzing the structure of antagonist elagolix bound GnRH1R published in Nature Communications in 2020. NAMs of GnRH1R can inhibit or block the GnRH1R signaling pathway, which is a potential drug target for GnRH1R and has certain social and economic value. The lack of the molecular mechanism for the negative allosteric modulators with GnRH1R is the main bottleneck in the development of negative allosteric modulator drugs. Therefore, we intend to report the high-resolution structure of furan-1 bound GnRH1R and furan-1 and 5-(N, N-hexamethylene) amiloride (HMA) bound GnRH1R by crystallography, and clarify the molecular mechanism of GnRH1R with NAMs combined with signal transduction experiments and molecular dynamics simulation.