5N1B

hPAD4 crystal complex with AFM-14a

5N1B の概要

• エントリーDOI: 10.2210/pdb5n1b/pdb
• 関連するPDBエントリー: 5N0M 5N0Y 5N0Z
• 分子名称: Protein-arginine deiminase type-4, SULFATE ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9UM07
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 75612.71

構造登録者

Beaumont, E.,Kerry, P.,Thompson, P.,Muth, A.,Subramanian, V.,Nagar, M.,Srinath, H.,Clancy, K.,Parelkar, S. (登録日: 2017-02-06, 公開日: 2017-05-24, 最終更新日: 2024-11-13)

主引用文献

Muth, A.,Subramanian, V.,Beaumont, E.,Nagar, M.,Kerry, P.,McEwan, P.,Srinath, H.,Clancy, K.,Parelkar, S.,Thompson, P.R.
Development of a Selective Inhibitor of Protein Arginine Deiminase 2.
J. Med. Chem., 60:3198-3211, 2017

PubMed Abstract: Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.

PubMed: 28328217
DOI: 10.1021/acs.jmedchem.7b00274

実験手法

X-RAY DIFFRACTION (2.9 Å)