5UE4

proMMP-9desFnII complexed to JNJ0966 INHIBITOR

5UE4 の概要

• エントリーDOI: 10.2210/pdb5ue4/pdb
• 関連するPDBエントリー: 5UE3
• 分子名称: Matrix metalloproteinase-9, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: prommp9, zymogen, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Secreted, extracellular space, extracellular matrix : P14780
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54136.11

構造登録者

Alexander, R.S.,Spurlino, J.,Milligan, C. (登録日: 2016-12-29, 公開日: 2017-09-13, 最終更新日: 2024-03-06)

主引用文献

Scannevin, R.H.,Alexander, R.,Haarlander, T.M.,Burke, S.L.,Singer, M.,Huo, C.,Zhang, Y.M.,Maguire, D.,Spurlino, J.,Deckman, I.,Carroll, K.I.,Lewandowski, F.,Devine, E.,Dzordzorme, K.,Tounge, B.,Milligan, C.,Bayoumy, S.,Williams, R.,Schalk-Hihi, C.,Leonard, K.,Jackson, P.,Todd, M.,Kuo, L.C.,Rhodes, K.J.
Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.
J. Biol. Chem., 292:17963-17974, 2017

PubMed Abstract: Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

PubMed: 28860188
DOI: 10.1074/jbc.M117.806075

実験手法

X-RAY DIFFRACTION (1.8 Å)