4HVA

Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6

Summary for 4HVA

• Entry DOI: 10.2210/pdb4hva/pdb
• Related PRD ID: PRD_000960
• Descriptor: Caspase-6, VEID Inhibitor, N-[(2R)-1-(3-cyanophenyl)-3-hydroxypropan-2-yl]-5-(3,4-dimethoxyphenyl)furan-3-carboxamide, ... (4 entities in total)
• Functional Keywords: caspase-6, active, veid, uncompetitive inhibition, ternary complex, caspase, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55212
• Total number of polymer chains: 4
• Total formula weight: 63327.06

Authors

Murray, J.M.,Steffek, M. (deposition date: 2012-11-05, release date: 2013-03-20, Last modification date: 2024-11-06)

Primary citation

Heise, C.E.,Murray, J.,Augustyn, K.E.,Bravo, B.,Chugha, P.,Cohen, F.,Giannetti, A.M.,Gibbons, P.,Hannoush, R.N.,Hearn, B.R.,Jaishankar, P.,Ly, C.Q.,Shah, K.,Stanger, K.,Steffek, M.,Tang, Y.,Zhao, X.,Lewcock, J.W.,Renslo, A.R.,Flygare, J.,Arkin, M.R.
Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.
Plos One, 7:e50864-e50864, 2012

PubMed Abstract: 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.

PubMed: 23227217
DOI: 10.1371/journal.pone.0050864

Experimental method

X-RAY DIFFRACTION (2.074 Å)