1A86

MMP8 WITH MALONIC AND ASPARTIC ACID BASED INHIBITOR

1A86 の概要

• エントリーDOI: 10.2210/pdb1a86/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000371
• 分子名称: MMP-8, N-benzyl-N~2~-[(2R)-2-(hydroxycarbamoyl)-4-methylpentanoyl]-L-alpha-asparagine, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: collagenase, matrix metalloproteinase, malonic acid, mmp8, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasmic granule: P22894
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18202.50

構造登録者

Brandstetter, H.,Roedern, E.G.V.,Grams, F.,Engh, R.A. (登録日: 1998-04-03, 公開日: 1999-05-04, 最終更新日: 2024-02-07)

主引用文献

Brandstetter, H.,Engh, R.A.,Von Roedern, E.G.,Moroder, L.,Huber, R.,Bode, W.,Grams, F.
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
Protein Sci., 7:1303-1309, 1998

PubMed Abstract: Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.

PubMed: 9655333

実験手法

X-RAY DIFFRACTION (2 Å)