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Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6

by Stanger, Karen , Bravo, Brandon , Zhao, Xianrui , Chugha, Preeti , Cohen, Frederick , Steffek, Micah , Augustyn, Katherine E. , Shah, Kinjalkumar , Arkin, Michelle R. , Heise, Christopher E. , Flygare, John , Murray, Jeremy , Jaishankar, Priyadarshini , Giannetti, Anthony M. , Hearn, Brian R. , Ly, Cuong Q. , Gibbons, Paul , Lewcock, Joseph W. , Hannoush, Rami N. , Tang, Yinyan , Renslo, Adam R.

in Acids / Amino Acid Sequence / Amino acids / Apoptosis / Biochemistry / Biology / Caspase / Caspase 6 - chemistry / Caspase 6 - metabolism / Caspase Inhibitors - analysis / Caspase Inhibitors - chemistry / Caspase Inhibitors - pharmacology / Caspase-3 / Caspase-6 / Chemistry / Crystal structure / Crystallography, X-Ray / Dehydrogenases / Drug Evaluation, Preclinical / Enzyme kinetics / Health aspects / Inhibitors / Kinases / Kinetics / Ligands / Models, Molecular / Molecular Sequence Data / Nervous system diseases / Neurodegenerative diseases / Neurological diseases / Peptides / Peptides - chemistry / Peptides - metabolism / Pharmacology / Protein Binding - drug effects / Proteins / Reproducibility of Results / Selectivity / Substrate inhibition / Substrate Specificity - drug effects / Surface Plasmon Resonance

2012

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Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6

2012

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2012

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Journal Article

Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6

Stanger, Karen,

Bravo, Brandon,

Zhao, Xianrui,

Chugha, Preeti,

Cohen, Frederick,

Steffek, Micah,

Augustyn, Katherine E.,

Shah, Kinjalkumar,

Arkin, Michelle R.,

Heise, Christopher E.,

Flygare, John,

Murray, Jeremy,

Jaishankar, Priyadarshini,

Giannetti, Anthony M.,

Hearn, Brian R.,

Ly, Cuong Q.,

Gibbons, Paul,

Lewcock, Joseph W.,

Hannoush, Rami N.,

Tang, Yinyan,

Renslo, Adam R.

2012

Overview

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.

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Publisher

Public Library of Science,Public Library of Science (PLoS)

Subject

Acids

/ Amino Acid Sequence

/ Amino acids

/ Apoptosis

/ Biochemistry

/ Biology

/ Caspase