Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, structure, and inhibition mechanism |
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Authors: | Schweizer Andreas Roschitzki-Voser Heidi Amstutz Patrick Briand Christophe Gulotti-Georgieva Maya Prenosil Eva Binz H Kaspar Capitani Guido Baici Antonio Plückthun Andreas Grütter Markus G |
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Institution: | Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. |
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Abstract: | Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network. |
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