| Autor: |
Christopher E Heise, Jeremy Murray, Katherine E Augustyn, Brandon Bravo, Preeti Chugha, Frederick Cohen, Anthony M Giannetti, Paul Gibbons, Rami N Hannoush, Brian R Hearn, Priyadarshini Jaishankar, Cuong Q Ly, Kinjalkumar Shah, Karen Stanger, Micah Steffek, Yinyan Tang, Xianrui Zhao, Joseph W Lewcock, Adam R Renslo, John Flygare, Michelle R Arkin |
| Jazyk: |
angličtina |
| Rok vydání: |
2012 |
| Předmět: |
|
| Zdroj: |
PLoS ONE, Vol 7, Iss 12, p e50864 (2012) |
| Druh dokumentu: |
article |
| ISSN: |
1932-6203 |
| DOI: |
10.1371/journal.pone.0050864 |
| Popis: |
Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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