5O7E

Crystal structure of the peptidase domain of collagenase H from Clostridium histolyticum in complex with N-aryl mercaptoacetamide-based inhibitor

5O7E の概要

• エントリーDOI: 10.2210/pdb5o7e/pdb
• 関連するPDBエントリー: 4arf
• 分子名称: ColH protein, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase-inhibitor complex, gluzincin, metalloprotease, collagenase, hydrolase
• 由来する生物種: Hathewaya histolytica
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46134.52

構造登録者

Schoenauer, E.,Brandstetter, H. (登録日: 2017-06-08, 公開日: 2018-01-31, 最終更新日: 2024-01-17)

主引用文献

Schonauer, E.,Kany, A.M.,Haupenthal, J.,Husecken, K.,Hoppe, I.J.,Voos, K.,Yahiaoui, S.,Elsasser, B.,Ducho, C.,Brandstetter, H.,Hartmann, R.W.
Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.
J. Am. Chem. Soc., 139:12696-12703, 2017

PubMed Abstract: Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed to achieve selectivity against human matrix metalloproteinases (MMPs). Using a surface plasmon resonance-based screening complemented with enzyme inhibition assays, we discovered an N-aryl mercaptoacetamide-based inhibitor scaffold that showed sub-micromolar affinities toward collagenase H (ColH) from the human pathogen Clostridium histolyticum. Moreover, these inhibitors also efficiently blocked the homologous bacterial collagenases, ColG from C. histolyticum, ColT from C. tetani, and ColQ1 from the Bacillus cereus strain Q1, while showing negligible activity toward human MMPs-1, -2, -3, -7, -8, and -14. The most active compound displayed a more than 1000-fold selectivity over human MMPs. This selectivity can be rationalized by the crystal structure of ColH with this compound, revealing a distinct non-primed binding mode to the active site. The non-primed binding mode presented here paves the way for the development of selective broad-spectrum bacterial collagenase inhibitors with potential therapeutic application in humans.

PubMed: 28820255
DOI: 10.1021/jacs.7b06935

実験手法

X-RAY DIFFRACTION (1.87 Å)