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5y3n

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Revision as of 07:57, 6 December 2017

Structure of TRAP1 complexed with DN401

Structural highlights

5y3n is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	TRAP1, HSP75 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhang L, Karsten P, Hamm S, Pogson JH, Muller-Rischart AK, Exner N, Haass C, Whitworth AJ, Winklhofer KF, Schulz JB, Voigt A. TRAP1 rescues PINK1 loss-of-function phenotypes. Hum Mol Genet. 2013 Jul 15;22(14):2829-41. doi: 10.1093/hmg/ddt132. Epub 2013 Mar, 21. PMID:23525905 doi:http://dx.doi.org/10.1093/hmg/ddt132
↑ Yoshida S, Tsutsumi S, Muhlebach G, Sourbier C, Lee MJ, Lee S, Vartholomaiou E, Tatokoro M, Beebe K, Miyajima N, Mohney RP, Chen Y, Hasumi H, Xu W, Fukushima H, Nakamura K, Koga F, Kihara K, Trepel J, Picard D, Neckers L. Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):E1604-12. doi:, 10.1073/pnas.1220659110. Epub 2013 Apr 5. PMID:23564345 doi:http://dx.doi.org/10.1073/pnas.1220659110
↑ Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, Calabrese F, Laudiero G, Esposito F, Landriscina M, Defilippi P, Bernardi P, Rasola A. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab. 2013 Jun 4;17(6):988-99. doi: 10.1016/j.cmet.2013.04.019. PMID:23747254 doi:http://dx.doi.org/10.1016/j.cmet.2013.04.019
↑ 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. Paralog specificity determines subcellular distribution, action mechanism, and anticancer activity of TRAP1 inhibitors. J Med Chem. 2017 Aug 17. doi: 10.1021/acs.jmedchem.7b00978. PMID:28816449 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00978

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5y3n"

@@ Line 3: / Line 3: @@
 <StructureSection load='5y3n' size='340' side='right' caption='[[5y3n]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5y3n]] is a 1 chain structure. 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 [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>
 </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>
+<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='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>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Jeong, H]]
 [[Category: Kang, B H]]

5y3n

From Proteopedia

Revision as of 07:57, 6 December 2017

Structure of TRAP1 complexed with DN401

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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