7vp9: Difference between revisions
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==Crystal structure of human ClpP in complex with ZG111== | ==Crystal structure of human ClpP in complex with ZG111== | ||
<StructureSection load='7vp9' size='340' side='right'caption='[[7vp9]]' scene=''> | <StructureSection load='7vp9' size='340' side='right'caption='[[7vp9]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VP9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7vp9]] is a 14 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VP9 FirstGlance]. <br> | ||
</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=7vp9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vp9 OCA], [https://pdbe.org/7vp9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vp9 RCSB], [https://www.ebi.ac.uk/pdbsum/7vp9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vp9 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7SR:(6S,9aS)-N-[(4-bromophenyl)methyl]-6-[(2S)-butan-2-yl]-8-(naphthalen-1-ylmethyl)-4,7-bis(oxidanylidene)-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide'>7SR</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Endopeptidase_Clp Endopeptidase Clp], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.92 3.4.21.92] </span></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=7vp9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vp9 OCA], [https://pdbe.org/7vp9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vp9 RCSB], [https://www.ebi.ac.uk/pdbsum/7vp9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vp9 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/CLPP_HUMAN CLPP_HUMAN]] Clp cleaves peptides in various proteins in a process that requires ATP hydrolysis. Clp may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP. | |||
Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.,Wang P, Zhang T, Wang X, Xiao H, Li H, Zhou LL, Yang T, Wei B, Zhu Z, Zhou L, Yang S, Lu X, Zhang Y, Huang Y, Gan J, Yang CG Cell Chem Biol. 2022 Jul 20. pii: S2451-9456(22)00245-8. doi:, 10.1016/j.chembiol.2022.07.002. PMID:35905743<ref>PMID:35905743</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7vp9" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Endopeptidase Clp]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gan | [[Category: Gan, J H]] | ||
[[Category: Wang | [[Category: Wang, P Y]] | ||
[[Category: Yang C | [[Category: Yang, C G]] | ||
[[Category: Hydrolase]] | |||
[[Category: Mitochondrial protease]] | |||