6deu: Difference between revisions

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-'''Unreleased structure'''
-The entry 6deu is ON HOLD
+==Human caspase-6 A109T==
+<StructureSection load='6deu' size='340' side='right'caption='[[6deu]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6deu]] is a 2 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=6DEU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DEU FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.796&#8491;</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=6deu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6deu OCA], [https://pdbe.org/6deu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6deu RCSB], [https://www.ebi.ac.uk/pdbsum/6deu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6deu 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 ==
+Caspase-6 is a cysteine protease that plays essential roles in programmed cell death, axonal degeneration, and development. The excess neuronal activity of Caspase-6 is associated with Alzheimer disease neuropathology and age-dependent cognitive impairment. Caspase-6 inhibition is a promising strategy to stop early stage neurodegenerative events, yet finding potent and selective Caspase-6 inhibitors has been a challenging task due to the overlapping structural and functional similarities between caspase family members. Here, we investigated how four rare non-synonymous missense single-nucleotide polymorphisms (SNPs), resulting in amino acid substitutions outside human Caspase-6 active site, affect enzyme structure and catalytic efficiency. Three investigated SNPs were found to align with a putative allosteric pocket with low sequence conservation among human caspases. Virtual screening of 57,700 compounds against the putative Caspase-6 allosteric pocket, followed by in vitro testing of the best virtual hits in recombinant human Caspase-6 activity assays identified novel allosteric Caspase-6 inhibitors with IC50 and Ki values ranging from ~2 to 13 microM. This report may pave the way towards the development and optimisation of novel small molecule allosteric Caspase-6 inhibitors and illustrates that functional characterisation of rare natural variants holds promise for the identification of allosteric sites on other therapeutic targets in drug discovery.
-Authors:
+Identification of Allosteric Inhibitors against Active Caspase-6.,Tubeleviciute-Aydin A, Beautrait A, Lynham J, Sharma G, Gorelik A, Deny LJ, Soya N, Lukacs GL, Nagar B, Marinier A, LeBlanc AC Sci Rep. 2019 Apr 2;9(1):5504. doi: 10.1038/s41598-019-41930-7. PMID:30940883<ref>PMID:30940883</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6deu" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Caspase 3D structures|Caspase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Beautrait A]]
+[[Category: Deny LJ]]
+[[Category: Gorelik A]]
+[[Category: LeBlanc AC]]
+[[Category: Lukacs GL]]
+[[Category: Lynham J]]
+[[Category: Marinier A]]
+[[Category: Nagar B]]
+[[Category: Sharma G]]
+[[Category: Soya N]]
+[[Category: Tubeleviciute-Aydin A]]