TAILIEUCHUNG - Báo cáo khoa học: Plasticity of S2–S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis

Many protein substrates of caspases are cleaved at noncanonical sites in comparison to the recognition motifs reported for the three caspase sub-groups. To provide insight into the specificity and aid in the design of drugs to control cell death, crystal structures of caspase-7 were determined in complexes with six peptide analogs (Ac-DMQD-Cho, Ac-DQMD-Cho, Ac-DNLD-Cho, Ac-IEPD-Cho, Ac-ESMD-Cho, Ac-WEHD-Cho) that span the major recognition motifs of the three subgroups. | ễFEBS Journal Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis Johnson Agniswamy Bin Fang and Irene T. Weber Department of Biology Molecular Basis of Disease Georgia State University Atlanta GA USA Keywords allosteric site apoptosis cysteine protease enzyme Correspondence I. T. Weber Department of Biology Georgia State University PO Box 4010 Atlanta GA 30302 USA Fax 1 404 413 5301 Tel 1 404 413 5411 E-mail iweber@ Database The atomic coordinates and structure factors have been deposited in the Protein Data Bank under the accession codes 2QL5 for caspase-7 DMQD 2QL9 for caspase-7 DQMD 2QLF for caspase-7 DNLD 2QL7 for caspase-7 IEPD 2QLB for caspase-7 ESMD and 2QLJ for caspase-7 WEHD Received 18 April2007 revised 3 July 2007 accepted 17 July 2007 doi Many protein substrates of caspases are cleaved at noncanonical sites in comparison to the recognition motifs reported for the three caspase subgroups. To provide insight into the specificity and aid in the design of drugs to control cell death crystal structures of caspase-7 were determined in complexes with six peptide analogs Ac-DMQD-Cho Ac-DQMD-Cho Ac-DNLD-Cho Ac-Il lI D-Clio Ac-ESMD-Cho Ac-WEHD-Cho that span the major recognition motifs of the three subgroups. The crystal structures show that the S2 pocket of caspase-7 can accommodate diverse residues. Glu is not required at the P3 position because Ac-DMQD-Cho Ac-DQMD-Cho and Ac-DNLD-Cho with varied P3 residues are almost as potent as the canonical Ac-DEVD-Cho. P4 Asp was present in the better inhibitors of caspase-7. However the S4 pocket of executioner caspase-7 has alternate regions for binding of small branched aliphatic or polar residues similar to those of initiator caspase-8. The observed plasticity of the caspase subsites agrees very well with the reported cleavage of many proteins at noncanonical sites. The results imply that factors other than the P4-P1 .

• Báo cáo khoa học
• Report medicine
• traditional medicine
• scientific reports
• oxidation
• chemical reaction
• tumor cells
• medical knowledge
• medical research
• analysis of cytoplasmic
• Crystal structure
• bacteria
• hemoglobin
• medicine
• cell proliferation
• breast cancer
• gastric cancer
• hormone medicine
• biochemical studies
• environmental medicine