[대학원 생명과학과 세미나 안내]
연사 : 조현수 교수(연세대학교 시스템생물학과)
연제 : Structure based drug discovery of Corticotropin-releasing hormone receptor 1 antagonist using X-ray Free-Electron Laser
일시 : 2022년 05월 13일 (금) 오후 4시 30분
장소 : 대면 및 온라인 화상 강의로 진행됩니다.
초청교수 : 송현규 교수
Abstract
Corticotropin-releasing hormone receptor 1 (CRF1) is an important drug target implicated in many stress-related diseases. There have been attempts to develop CRF1 target drugs, but no success yet. Recently, many pharmaceutical companies have been focusing on drug development research using high-resolution GPCR structures. The development of X-ray free-electron lasers (XFELs) has further accelerated structural studies of GPCRs, preventing radiation damage and providing access to high-resolution structures. Here, we report the crystal structure of CRF1 complexed with BMK-I-152 antagonist at 2.75 Å by fixed-target serial femtosecond crystallography. The structure reveals unique two hydrogen bonds in the hydrogen bond network, the alpha helix form of the stalk region and antagonist binding in the hydrophobic network. Based on the structure we developed two antagonists BMK-C203 and BMK-C205, and determined complex structures of CRF1 with both BMK-C203 and BMK-C205 at 2.6 Å and 2.2 Å resolution, respectively. Our result shows that BMK-C205 has significant anti-depressant effects in mice, thus could be utilized further among structure-based drug discovery of CRF1.