9DOP

Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site

これはPDB形式変換不可エントリーです。

9DOP の概要

• エントリーDOI: 10.2210/pdb9dop/pdb
• 関連するPDBエントリー: 9DOL
• 分子名称: Protein-arginine deiminase type-4, CALCIUM ION, (2R)-2-amino-2-{1-[(5M)-5-(3,5-dichloropyridin-2-yl)isoquinolin-1-yl]piperidin-4-yl}-1-(pyrrolidin-1-yl)ethan-1-one, ... (4 entities in total)
• 機能のキーワード: peptyl arginine deiminase, inhibitor, allosteric, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 75490.40

構造登録者

Liu, S. (登録日: 2024-09-19, 公開日: 2025-05-28)

主引用文献

Dakin, L.A.,Xing, L.,Hall, J.,Ding, W.,Vajdos, F.F.,Pelker, J.W.,Ramsey, S.,Balbo, P.,Sahasrabudhe, P.V.,Banker, M.E.,Choi, W.Y.,Wright, S.W.,Chang, J.S.,Curto, J.M.,Davoren, J.E.,Drozda, S.E.,Fennell, K.F.,Futatsugi, K.,Kortum, S.,Lee, K.L.,Liu, S.,Lovering, F.,Nicki, J.A.,Trujillo, J.I.,Vincent, F.,Schnute, M.E.
Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca 2+ dependent allosteric binding site.
Nat Commun, 16:4579-4579, 2025

PubMed Abstract: Peptidylarginine deiminases (PAD1-4) are calcium dependent enzymes responsible for protein citrullination, a post-translational modification converting arginine residues to citrulline. Elevated levels of citrullinated proteins have been associated with rheumatoid arthritis, neurodegenerative diseases, and cancers. Though highly selective PAD4 inhibitors have been described, inhibitors to the broader family currently are limited to covalent substrate analogs. Herein, we describe an allosteric binding pocket common to PAD1-4 suitable for the identification of potent, non-covalent enzyme inhibitors. A ligand-based virtual screen is utilized to identify a PAD4 inhibitor for which surface plasmon resonance confirms target binding but non-competitively with a known PAD4 ligand. We further show through co-crystal structure analysis that the ligand binds PAD4 at an allosteric pocket resulting in stabilization of a catalytically inactive, calcium-deficient enzyme conformation. A ligand designed based on this site potently inhibits all four PAD isozymes and prevents protein citrullination in neutrophils with a broader protein repertoire than observed with a PAD4-selective inhibitor.

PubMed: 40379660
DOI: 10.1038/s41467-025-59919-4

実験手法

X-RAY DIFFRACTION (2.44 Å)