View source for 8dj3


==Caspase-7 bound to novel allosteric inhibitor==
<StructureSection load='8dj3' size='340' side='right'caption='[[8dj3]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dj3]] 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=8DJ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DJ3 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]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SE1:2-[(2-{[(3s,5s,7s)-adamantan-1-yl]sulfamoyl}phenyl)sulfanyl]benzoic+acid'>SE1</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=8dj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dj3 OCA], [https://pdbe.org/8dj3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dj3 RCSB], [https://www.ebi.ac.uk/pdbsum/8dj3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dj3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CASP7_HUMAN CASP7_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Overexpression promotes programmed cell death.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Caspase-7 (C7), a cysteine protease involved in apoptosis, is a valuable drug target for its role in human diseases (e. g., Parkinson's, Alzheimer's, sepsis). The C7 allosteric site has great potential for small-molecule targeting, but numerous drug discovery efforts have identified precious few allosteric inhibitors. Here we present the first selective, drug-like inhibitor of C7 along with several other improved inhibitors based on our previous fragment hit. We also provide a rational basis for the impact of allosteric binding on the C7 catalytic cycle by using an integrated approach including X-ray crystallography, stopped-flow kinetics, and molecular dynamics simulations. Our findings suggest allosteric binding disrupts C7 pre-acylation by neutralization of the catalytic dyad, displacement of substrate from the oxyanion hole, and altered dynamics of substrate binding loops. This work advances drug targeting efforts and bolsters our understanding of allosteric structure-activity relationships (ASARs).

Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power.,Hobbs KF, Propp J, Vance NR, Kalenkiewicz A, Witkin KR, Ashley Spies M Chemistry. 2023 Apr 2:e202300872. doi: 10.1002/chem.202300872. PMID:37005499<ref>PMID:37005499</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dj3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kalenkiewicz A]]
[[Category: Kathryn FH]]
[[Category: Propp J]]
[[Category: Spies MA]]