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| | <StructureSection load='6dl7' size='340' side='right'caption='[[6dl7]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='6dl7' size='340' side='right'caption='[[6dl7]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dl7]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DL7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DL7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dl7]] is a 7 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=6DL7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DL7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ONC:7-benzyl-4-[(2-methylphenyl)methyl]-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one'>ONC</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CLPP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ONC:7-benzyl-4-[(2-methylphenyl)methyl]-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one'>ONC</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Endopeptidase_Clp Endopeptidase Clp], with EC number [http://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=6dl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dl7 OCA], [https://pdbe.org/6dl7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dl7 RCSB], [https://www.ebi.ac.uk/pdbsum/6dl7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dl7 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dl7 OCA], [http://pdbe.org/6dl7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dl7 RCSB], [http://www.ebi.ac.uk/pdbsum/6dl7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dl7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
| + | |
| - | | + | |
| - | Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.,Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, Zhao R, St-Germain J, Heese LE, Egan G, Ruvolo VR, Barghout SH, Nishida Y, Hurren R, Ma W, Gronda M, Link T, Wong K, Mabanglo M, Kojima K, Borthakur G, MacLean N, Ma MCJ, Leber AB, Minden MD, Houry W, Kantarjian H, Stogniew M, Raught B, Pai EF, Schimmer AD, Andreeff M Cancer Cell. 2019 May 13;35(5):721-737.e9. doi: 10.1016/j.ccell.2019.03.014. Epub, 2019 May 2. PMID:31056398<ref>PMID:31056398</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6dl7" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Clp protease 3D structures|Clp protease 3D structures]] | | *[[Clp protease 3D structures|Clp protease 3D structures]] |
| - | == References == | |
| - | <references/> | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Endopeptidase Clp]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Halgas, O]] | + | [[Category: Halgas O]] |
| - | [[Category: Pai, E F]] | + | [[Category: Pai EF]] |
| - | [[Category: Schimmer, A]] | + | [[Category: Schimmer A]] |
| - | [[Category: Zarabi, S F]] | + | [[Category: Zarabi SF]] |
| - | [[Category: Degradation]]
| + | |
| - | [[Category: Homeostasis]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Mitochondria]]
| + | |
| - | [[Category: Protease]]
| + | |
