TY - JOUR
AU - Michelle R., Arkin
AB - 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.
TI - Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6
JF - PLoS ONE
DO - 10.1371/journal.pone.0050864
DA - 2012-12-05
UR - https://www.deepdyve.com/lp/public-library-of-science-plos-journal/mechanistic-and-structural-understanding-of-uncompetitive-inhibitors-aXy0DW4Fva
VL - 7
IS - 12
DP - DeepDyve
ER -