8JUF

Crystal structure of human MMP-7 in complex with inhibitor

8JUF の概要

• エントリーDOI: 10.2210/pdb8juf/pdb
• 分子名称: Matrilysin, Peptide Inhibitor, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: matrilysin, matrin, matrix metalloproteinase-7, pump-1 protease, uterine metalloproteinase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 20372.95

構造登録者

Kamitani, M.,Abe-Sato, K.,Oka, Y. (登録日: 2023-06-26, 公開日: 2023-11-01, 最終更新日: 2023-11-22)

主引用文献

Abe-Sato, K.,Tabuse, H.,Kanazawa, H.,Kamitani, M.,Endo, M.,Tokura, S.,Wakabayashi, S.,Yahara, T.,Takeda, T.,Hitaka, K.,Gunji, E.,Kojima, N.,Oka, Y.
Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis.
J.Med.Chem., 66:14653-14668, 2023

PubMed Abstract: Matrix metalloproteinase-7 (MMP-7) has been shown to play important roles in pathophysiological processes involved in the development/progression of diseases such as cancer and fibrosis. We discovered selective MMP-7 inhibitors composed of arylsulfonamide, carboxylate, and short peptides by a molecular hybridization approach. These compounds interacted with MMP-7 via multiple hydrogen bonds in the cocrystal structures. To obtain compounds for evaluation, we attempted structural optimization, particularly targeting Tyr167 at the S3 subsite through structure-based drug design, and identified compound as showing improved MMP-7 potency and MMP subtype selectivity. A novel π-π stacking interaction with Tyr167 was achieved when 4-pyridylalanine was introduced as the P3 residue. Compound suppressed the progression of kidney fibrosis in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Thus, we demonstrated, for the first time, that potent and selective MMP-7 inhibitors could prevent the progression of kidney fibrosis.

PubMed: 37861435
DOI: 10.1021/acs.jmedchem.3c01166

実験手法

X-RAY DIFFRACTION (1.39 Å)