5O7E
Crystal structure of the peptidase domain of collagenase H from Clostridium histolyticum in complex with N-aryl mercaptoacetamide-based inhibitor
Summary for 5O7E
| Entry DOI | 10.2210/pdb5o7e/pdb |
| Related | 4arf |
| Descriptor | ColH protein, ZINC ION, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | hydrolase-inhibitor complex, gluzincin, metalloprotease, collagenase, hydrolase |
| Biological source | Hathewaya histolytica |
| Total number of polymer chains | 1 |
| Total formula weight | 46134.52 |
| Authors | Schoenauer, E.,Brandstetter, H. (deposition date: 2017-06-08, release date: 2018-01-31, Last modification date: 2024-01-17) |
| Primary citation | 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 Cited by 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: 28820255DOI: 10.1021/jacs.7b06935 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.87 Å) |
Structure validation
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