Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea.
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
Exp Mol Med. 2023 Sep;55(9):2039-2050. doi: 10.1038/s12276-023-01082-1. Epub 2023 Sep 1.
Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRFR), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRFR complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists-BMK-C203 and BMK-C205-and determined the CRFR/BMK-C203 and CRFR/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRFR.
迄今为止，开发靶向促肾上腺皮质激素释放激素受体 1 (CRFR)的药物的尝试都没有成功，CRFR 是应激相关治疗的一个药物靶点。研究集中于使用高分辨率的 G 蛋白偶联受体 (GPCR) 结构来开发药物。X 射线自由电子激光 (XFEL) 可防止辐射损伤并提供高分辨率结构的获取途径，有助于加速 GPCR 结构研究。我们使用固定靶连续飞秒晶体学解析了与 BMK-I-152 拮抗剂结合的 CRFR 复合物的晶体结构，分辨率为 2.75 Å。结果表明，氢键网络中存在两个独特的氢键，柄区形成一个α螺旋，疏水区包含一个拮抗剂结合位点。我们随后开发了两种拮抗剂 BMK-C203 和 BMK-C205，并分别解析了 CRFR/BMK-C203 和 CRFR/BMK-C205 复合物的结构，分辨率分别为 2.6 和 2.2 Å。BMK-C205 在小鼠中表现出显著的抗抑郁作用，因此，可能被用于有效鉴定针对 CRFR 的基于结构的药物。
