5D3C

Crystal structure of a double mutant catalytic domain of Human MMP12 in complex with an hydroxamate analogue of RXP470

5D3C の概要

• エントリーDOI: 10.2210/pdb5d3c/pdb
• 分子名称: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: mmp12, human, macrophage metalloelastase, rxp470, hydroxamate, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted, extracellular space, extracellular matrix : P39900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18466.68

構造登録者

Rouanet-Mehouas, C.,Devel, L.,Dive, V.,Stura, E.A. (登録日: 2015-08-06, 公開日: 2016-08-17, 最終更新日: 2024-01-10)

主引用文献

Rouanet-Mehouas, C.,Czarny, B.,Beau, F.,Cassar-Lajeunesse, E.,Stura, E.A.,Dive, V.,Devel, L.
Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.
J. Med. Chem., 60:403-414, 2017

PubMed Abstract: The most exploited strategy to develop potent zinc-metalloprotease inhibitors relies on a core zinc chelator and a peptidic or nonpeptidic scaffold that provides supplementary interactions for optimized potency and selectivity. Applied to matrix metalloproteases (MMPs) with highly conserved catalytic domains, this strategy failed to identify inhibitors with the desired selectivity profiles. To question the precise role of the zinc-binding group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but different ZBGs. We find that exchanging the ZBG modifies inhibitor positioning and affects its dynamics and selectivity. The binding properties of these compounds were compared through biochemical, structural, and calorimetric studies, showing a complex interplay between cooperative interactions and dynamics dictated by the ZBG. Improving selectivity will require expanding the ZBG repertoire within inhibitor libraries, since relying on a single ZBG significantly decreases our chance to identify effective inhibitors.

PubMed: 27996256
DOI: 10.1021/acs.jmedchem.6b01420

実験手法

X-RAY DIFFRACTION (1.314 Å)