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==Structure of TRAP1 complexed with DN401==
==Structure of TRAP1 complexed with DN401==
<StructureSection load='5y3n' size='340' side='right' caption='[[5y3n]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='5y3n' size='340' side='right'caption='[[5y3n]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5y3n]] is a 1 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=5Y3N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y3N FirstGlance]. <br>
<table><tr><td colspan='2'>[[5y3n]] is a 1 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=5Y3N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Y3N FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8MF:1-[(6-bromanyl-1,3-benzodioxol-5-yl)methyl]-4-chloranyl-pyrazolo[3,4-d]pyrimidin-6-amine'>8MF</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]] 2.4&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRAP1, HSP75 ([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=8MF:1-[(6-bromanyl-1,3-benzodioxol-5-yl)methyl]-4-chloranyl-pyrazolo[3,4-d]pyrimidin-6-amine'>8MF</scene></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=5y3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y3n OCA], [http://pdbe.org/5y3n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y3n RCSB], [http://www.ebi.ac.uk/pdbsum/5y3n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y3n ProSAT]</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=5y3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y3n OCA], [https://pdbe.org/5y3n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5y3n RCSB], [https://www.ebi.ac.uk/pdbsum/5y3n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5y3n ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/TRAP1_HUMAN TRAP1_HUMAN]] Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, most likely through stabilization of mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.<ref>PMID:23525905</ref> <ref>PMID:23564345</ref> <ref>PMID:23747254</ref>
[https://www.uniprot.org/uniprot/TRAP1_HUMAN TRAP1_HUMAN] Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, most likely through stabilization of mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.<ref>PMID:23525905</ref> <ref>PMID:23564345</ref> <ref>PMID:23747254</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor BIIB021 was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 3b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 3b can potentially be exploited to design a potent TRAP1 inhibitor.


Paralog specificity determines subcellular distribution, action mechanism, and anticancer activity of TRAP1 inhibitors.,Park HK, Jeong H, Ko E, Lee G, Lee JE, Lee SK, Lee AJ, Im JY, Hu S, Kim SH, Lee JH, Lee C, Kang S, Kang BH J Med Chem. 2017 Aug 17. doi: 10.1021/acs.jmedchem.7b00978. PMID:28816449<ref>PMID:28816449</ref>
==See Also==
 
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5y3n" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Jeong, H]]
[[Category: Large Structures]]
[[Category: Kang, B H]]
[[Category: Jeong H]]
[[Category: Kang, S]]
[[Category: Kang BH]]
[[Category: Lee, C]]
[[Category: Kang S]]
[[Category: Park, H K]]
[[Category: Lee C]]
[[Category: Chaperone]]
[[Category: Park HK]]
[[Category: Dn401]]
[[Category: Inhibitor]]
[[Category: Mitochondrial hsp90]]
[[Category: Trap1]]
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