한빛사논문
- 조회530
Hoyoung Kim 1,8, Taehyun Lim 2,8, Go Eun Ha 3,8, Jee-Young Lee 4, Jun-Woo Kim 4, Nienping Chang 1, Si Hyun Kim 5,6, Ki Hun Kim 5, Jaeick Lee 5, Yongju Cho 1, Byeong Wook Kim 2, Alva Abrahamsson 2, Sung Hwan Kim 4, Hyo-Ji Kim 4, Sehan Park 7, Sang Jae Lee 7, Jaehyun Park 7, Eunji Cheong 3,9,*, B. Moon Kim 2,9,* and Hyun-Soo Cho 1,9,*
1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seoul 03722, Republic of Korea.
2Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
3Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
4New Drug Development Center (NDDC), Daegu Gyeongbuk Medical Innovation Foundation (K-Medi hub), 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea.
5Doping Control Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
6Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
7Pohang Accelerator Laboratory, POSTECH, Pohang 37673, Republic of Korea.
8These authors contributed equally: Hoyoung Kim, Taehyun Lim, Go Eun Ha.
9These authors jointly supervised this work: Eunji Cheong, B. Moon Kim, Hyun-Soo Cho.
*Corresponding author: correspondence to Eunji Cheong, B. Moon Kim or Hyun-Soo Cho
Abstract
Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), 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 CRF1R 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 CRF1R/BMK-C203 and CRF1R/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 CRF1R.
논문정보
- Research article
- 2023년 09월 (BRIC 등록일 2023-09-06)
- 국내 연구진
- 생명과학 > 생화학
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