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KMID : 0620920230550092039
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Experimental & Molecular Medicine
2023 Volume.55 No. 9 p.2039 ~ p.2050
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Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser
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Kim Ho-Young
Lim Tae-Hyun
Ha Go-Eun
Lee Jee-Young
Kim Jun-Woo
Nienping Chang
Kim Si-Hyun
Kim Ki-Hun
Lee Jae-Ick
Cho Yong-Ju
Kim Byeong-Wook
Alva Abrahamsson
Kim Sung-Hwan
Kim Hyo-Ji
Park Se-Han
Lee Sang-Jae
Park Jae-Hyun
Cheong Eun-Ji
B Moon Kim
Cho Hyun-Soo
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Abstract
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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?A 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?A, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.
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KEYWORD
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Drug delivery, Protein?protein interaction networks
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