Conformational restrictions in the active site of unliganded human caspase-3

2003 ◽  
Vol 16 (3) ◽  
pp. 121-124 ◽  
Author(s):  
Chao-Zhou Ni ◽  
Chenglong Li ◽  
Joe C. Wu ◽  
Alfred P. Spada ◽  
Kathryn R. Ely
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Human Caspase ◽  
Conformational Restrictions

scholarly journals Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

2018 ◽  
Author(s):  
R. N. V. Krishna Deepak ◽  
Ahmad Abdullah ◽  
Priti Talwar ◽  
Hao Fan ◽  
Palaniyandi Ravanan
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Specific Activity ◽  
Special Importance ◽  
Allosteric Inhibitors ◽  
Dimerization Interface ◽  
Executioner Caspases ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractThe regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

CO2 impairs peroxynitrite-mediated inhibition of human caspase-3

2006 ◽  
Vol 349 (1) ◽  
pp. 367-371 ◽  
Author(s):  
Paolo Ascenzi ◽  
Maria Marino ◽  
Enea Menegatti
Keyword(s):  
Caspase 3 ◽  
Human Caspase

scholarly journals Labeling of apoptotic JURL-MK1 cells by fluorescent caspase-3 inhibitor FAM-DEVD-fmk occurs mainly at site(s) different from caspase-3 active site

2007 ◽  
Vol 71A (8) ◽  
pp. 605-611 ◽  
Author(s):  
Kateřina Kuželová ◽  
Dana Grebeňová ◽  
Zbyněk Hrkal
Keyword(s):  
Active Site ◽  
Caspase 3

scholarly journals S-Nitrosylation of mitochondrial caspases

2001 ◽  
Vol 154 (6) ◽  
pp. 1111-1116 ◽  
Author(s):  
Joan B. Mannick ◽  
Christopher Schonhoff ◽  
Natalia Papeta ◽  
Pedram Ghafourifar ◽  
Marten Szibor ◽  
...  
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Resting Cells ◽  
Intermembrane Space ◽  
Caspase 9 ◽  
Active Site Cysteine ◽  
Mitochondrial Intermembrane Space ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Central Effector

Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. In resting cells, a subset of caspase-3 zymogens is S-nitrosylated at the active site cysteine, inhibiting enzyme activity. During Fas-induced apoptosis, caspases are denitrosylated, allowing the catalytic site to function. In the current studies, we sought to identify the subpopulation of caspases that is regulated by S-nitrosylation. We report that the majority of mitochondrial, but not cytoplasmic, caspase-3 zymogens contain this inhibitory modification. In addition, the majority of mitochondrial caspase-9 is S-nitrosylated. These studies suggest that S-nitrosylation plays an important role in regulating mitochondrial caspase function and that the S-nitrosylation state of a given protein depends on its subcellular localization.

scholarly journals Biochemical and Genetic Interactions betweenDrosophila Caspases and the Proapoptotic Genesrpr, hid, and grim

2000 ◽  
Vol 20 (8) ◽  
pp. 2907-2914 ◽  
Author(s):  
Zhiwei Song ◽  
Bo Guan ◽  
Andreas Bergman ◽  
Donald W. Nicholson ◽  
Nancy A. Thornberry ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cultured Cells ◽  
Ectopic Expression ◽  
Full Length ◽  
Truncated Form ◽  
Effector Caspase ◽  
Death Effector ◽  
Human Caspase

ABSTRACT In Drosophila melanogaster, the induction of apoptosis requires three closely linked genes, reaper(rpr), head involution defective(hid), and grim. The products of these genes induce apoptosis by activating a caspase pathway. Two very similarDrosophila caspases, DCP-1 and drICE, have been previously identified. We now show that DCP-1 has a substrate specificity that is remarkably similar to those of human caspase 3 and Caenorhabditis elegans CED-3, suggesting that DCP-1 is a death effector caspase. drICE and DCP-1 have similar yet different enzymatic specificities. Although expression of either in cultured cells induces apoptosis, neither protein was able to induce DNA fragmentation inDrosophila SL2 cells. Ectopic expression of a truncated form of dcp-1 (ΔN-dcp-1) in the developingDrosophila retina under an eye-specific promoter resulted in a small and rough eye phenotype, whereas expression of the full-length dcp-1 (fl-dcp-1) had little effect. On the other hand, expression of either full-length drICE(fl-drICE) or truncated drICE(ΔN-drICE) in the retina showed no obvious eye phenotype. Although active DCP-1 protein cleaves full-length DCP-1 and full-length drICE in vitro, GMR-ΔN-dcp-1 did not enhance the eye phenotype of GMR-fl-dcp-1 or GMR-fl-drICEflies. Significantly, GMR-rpr and GMR-grim, but not GMR-hid, dramatically enhanced the eye phenotype of GMR-fl-dcp-1 flies. These results indicate that Reaper and Grim, but not HID, can activate DCP-1 in vivo.

scholarly journals Functional Analysis of the Inhibitor of Apoptosis (iap) Gene Carried by the Entomopoxvirus of Amsacta moorei

2005 ◽  
Vol 79 (4) ◽  
pp. 2335-2345 ◽  
Author(s):  
Qianjun Li ◽  
Peter Liston ◽  
Richard W. Moyer
Keyword(s):  
Caspase 3 ◽  
Autographa Californica ◽  
Inhibitor Of Apoptosis ◽  
Intrinsic Pathway ◽  
Abortive Infection ◽  
Caspase 9 ◽  
Rapid Induction ◽  
Human Caspase ◽  
Proapoptotic Gene

ABSTRACT The entomopoxvirus from Amsacta moorei (AmEPV) contains none of the commonly recognized vertebrate poxvirus apoptotic suppressor genes. However, AmEPV carries a single inhibitor of apoptosis (iap) gene (AMViap) not present in vertebrate poxviruses. The AMViap gene was active when coexpressed with the Drosophila proapoptotic gene hid in Ld652 cells and can rescue cells from apoptosis as shown by increased number of surviving cells and reduced levels of caspase-3-like activity. We also showed that expression of the AMViap gene rescued polyhedron production in Autographa californica M nucleopolyhedrovirus (AcMNPV)Δp35-infected Sf9 cells during an otherwise abortive infection induced by apoptosis. Surprisingly, deletion of the AMViap gene from the AmEPV genome led to only a modest (10-fold) loss of virion production in infected Ld652 cells, indicating that the AMViap gene is nonessential for virus replication under these conditions. However, infection of Ld652 cells by AmEPV lacking a functional iap gene led to a more rapid induction of cytotoxicity and increased levels of caspase-3-like activity. Similar results were observed and were more pronounced in infected Sf9 and S2 cells. The purified AMVIAP protein also inhibits the enzymatic activities of human caspase-9 and caspase-3 in vitro. Our results indicate that while the AMViap gene was active in controlling apoptosis through the intrinsic pathway, the virus likely encodes additional proteins that also regulate apoptosis.

Human caspase-3 inhibition by Z-tLeu-Asp-H: tLeu(P2) counterbalances Asp(P4) and Glu(P3) specific inhibitor truncation

2008 ◽  
Vol 377 (3) ◽  
pp. 757-762 ◽  
Author(s):  
Patrizia Colantonio ◽  
Loris Leboffe ◽  
Alessandro Bolli ◽  
Maria Marino ◽  
Paolo Ascenzi ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Specific Inhibitor ◽  
Human Caspase

Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine

2005 ◽  
Vol 1 (3) ◽  
pp. 154-158 ◽  
Author(s):  
Douglas A Mitchell ◽  
Michael A Marletta
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Active Site Cysteine
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