8GOD

Co-crystal structure of Human Protein-arginine deiminase type-4 (PAD4) with small molecule inhibitor JBI-589

8GOD の概要

• エントリーDOI: 10.2210/pdb8god/pdb
• 分子名称: Protein-arginine deiminase type-4, [(3~{R})-3-azanylpiperidin-1-yl]-[2-[1-[(4-fluorophenyl)methyl]indol-2-yl]-3-methyl-imidazo[1,2-a]pyridin-7-yl]methanone (3 entities in total)
• 機能のキーワード: small molecule inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 77801.07

構造登録者

Swaminathan, S.,Birudukota, S.,Vaithilingam, K.,Kandan, S.,Asaithambi, K.,Kathiresan, N.,Gosu, R.,Rajagopal, S.,Sadhu, N. (登録日: 2022-08-24, 公開日: 2023-03-29, 最終更新日: 2023-11-29)

主引用文献

Gajendran, C.,Fukui, S.,Sadhu, N.M.,Zainuddin, M.,Rajagopal, S.,Gosu, R.,Gutch, S.,Fukui, S.,Sheehy, C.E.,Chu, L.,Vishwakarma, S.,Jeyaraj, D.A.,Hallur, G.,Wagner, D.D.,Sivanandhan, D.
Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4.
Sci Rep, 13:3189-3189, 2023

PubMed Abstract: Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 - deficient mice have shown that PAD4 deficiency does not lead to increased infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is associated with a number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88 Å resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.

PubMed: 36823444
DOI: 10.1038/s41598-023-30246-2

実験手法

X-RAY DIFFRACTION (2.88 Å)