6EOX

Crystal structure of MMP12 in complex with carboxylic inhibitor LP165.

6EOX の概要

• エントリーDOI: 10.2210/pdb6eox/pdb
• 関連するPDBエントリー: 6EKN 6ELA 6ENM
• 分子名称: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: metzincin, carboxylate inhibitor alternative zinc-binding groups, 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: 18249.15

構造登録者

Vera, L.,Nuti, E.,Rossello, A.,Stura, E.A. (登録日: 2017-10-10, 公開日: 2018-05-16, 最終更新日: 2024-01-17)

主引用文献

Nuti, E.,Cuffaro, D.,Bernardini, E.,Camodeca, C.,Panelli, L.,Chaves, S.,Ciccone, L.,Tepshi, L.,Vera, L.,Orlandini, E.,Nencetti, S.,Stura, E.A.,Santos, M.A.,Dive, V.,Rossello, A.
Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.
J. Med. Chem., 61:4421-4435, 2018

PubMed Abstract: Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results.

PubMed: 29727184
DOI: 10.1021/acs.jmedchem.8b00096

実験手法

X-RAY DIFFRACTION (1.3 Å)