8eg6: Difference between revisions
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==huCaspase-6 in complex with inhibitor 2a== | |||
<StructureSection load='8eg6' size='340' side='right'caption='[[8eg6]], [[Resolution|resolution]] 1.82Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8eg6]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EG6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EG6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=US9:(3R)-1-(ethanesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxamide'>US9</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8eg6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8eg6 OCA], [https://pdbe.org/8eg6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8eg6 RCSB], [https://www.ebi.ac.uk/pdbsum/8eg6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8eg6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CASP6_HUMAN CASP6_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases. | |||
Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.,Van Horn KS, Wang D, Medina-Cleghorn D, Lee PS, Bryant C, Altobelli C, Jaishankar P, Leung KK, Ng RA, Ambrose AJ, Tang Y, Arkin MR, Renslo AR J Am Chem Soc. 2023 Apr 27. doi: 10.1021/jacs.2c12240. PMID:37104712<ref>PMID:37104712</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8eg6" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Altobelli C]] | |||
[[Category: Ambrose AJ]] | |||
[[Category: Arkin MR]] | |||
[[Category: Bryant C]] | |||
[[Category: Fan P]] | |||
[[Category: Jaishankar P]] | |||
[[Category: Lee P]] | |||
[[Category: Liu J]] | |||
[[Category: Medina-Cleghorn D]] | |||
[[Category: Ng RA]] | |||
[[Category: Renslo AR]] | |||
[[Category: Tang Y]] | |||
[[Category: Van Horn K]] | |||
[[Category: Wang D]] | |||
[[Category: Wang Y]] | |||
[[Category: Zhao Y]] | |||
Revision as of 09:55, 10 May 2023
huCaspase-6 in complex with inhibitor 2ahuCaspase-6 in complex with inhibitor 2a
Structural highlights
FunctionCASP6_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMedCaspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.,Van Horn KS, Wang D, Medina-Cleghorn D, Lee PS, Bryant C, Altobelli C, Jaishankar P, Leung KK, Ng RA, Ambrose AJ, Tang Y, Arkin MR, Renslo AR J Am Chem Soc. 2023 Apr 27. doi: 10.1021/jacs.2c12240. PMID:37104712[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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