3P8E

Crystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithine

3P8E の概要

• エントリーDOI: 10.2210/pdb3p8e/pdb
• 関連するPDBエントリー: 3I2E 3I4A 3P8P
• 分子名称: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1, N~5~-[(1S)-1-aminopentyl]-L-ornithine (3 entities in total)
• 機能のキーワード: ddah, nitric oxide synthase regulation, 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: 2
• 化学式量合計: 67681.60

構造登録者

Lluis, M.,Wang, Y.,Monzingo, A.F.,Fast, W.,Robertus, J.D. (登録日: 2010-10-13, 公開日: 2010-11-10, 最終更新日: 2023-09-06)

主引用文献

Lluis, M.,Wang, Y.,Monzingo, A.F.,Fast, W.,Robertus, J.D.
Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1.
Chemmedchem, 6:81-88, 2011

PubMed Abstract: C-Alkyl amidine analogues of asymmetric N(ω),N(ω)-dimethyl-L-arginine are dual-targeted inhibitors of both human DDAH-1 and nitric oxide (NO) synthase, and provide a promising scaffold for the development of therapeutics to control NO overproduction in a variety of pathologies including septic shock and some cancers. Using a two-part click-chemistry-mediated activity probe, a homologated series of C-alkyl amidines were ranked for their ability to inhibit DDAH-1 within cultured HEK 293T cells. N⁵-(1-Iminopentyl)-L-ornithine was determined to be the most potent compound in vitro (K(d)=7 μM) as well as in cultured cells, and the binding conformation and covalent reversible mode of inhibition was investigated by comparison of interactions made with DDAH-1 and a catalytically inactive C274S variant, as gauged by X-ray crystallography and isothermal titration calorimetry. By interrupting the ability of the inhibitor to form a covalent bond, the contribution of this interaction could be estimated. These results suggest that further stabilization of the covalent adduct is a promising strategy for lead optimization in the design of effective reagents to block NO synthesis.

PubMed: 20979083
DOI: 10.1002/cmdc.201000392

実験手法

X-RAY DIFFRACTION (2.4946 Å)