4z1f

From Proteopedia

(Difference between revisions)

Revision as of 12:44, 22 April 2015

Crystal structure of human Trap1 with PU-H71

Structural highlights

4z1f is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4z1g, 4z1h, 4z1i
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.

Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1.,Lee C, Park HK, Jeong H, Lim J, Lee AJ, Cheon KY, Kim CS, Thomas AP, Bae B, Kim ND, Kim SH, Suh PG, Ryu JH, Kang BH J Am Chem Soc. 2015 Apr 8;137(13):4358-67. doi: 10.1021/ja511893n. Epub 2015 Mar , 30. PMID:25785725^[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
↑ Lee C, Park HK, Jeong H, Lim J, Lee AJ, Cheon KY, Kim CS, Thomas AP, Bae B, Kim ND, Kim SH, Suh PG, Ryu JH, Kang BH. Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1. J Am Chem Soc. 2015 Apr 8;137(13):4358-67. doi: 10.1021/ja511893n. Epub 2015 Mar , 30. PMID:25785725 doi:http://dx.doi.org/10.1021/ja511893n

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/4z1f"

Categories: Kang, B H | Lee, C | Park, H K | Ryu, J H | Mitochondrial hsp90

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Crystal structure of human Trap1 with PU-H71==
+<StructureSection load='4z1f' size='340' side='right' caption='[[4z1f]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4z1f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z1F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z1F FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H71:8-[(6-IODO-1,3-BENZODIOXOL-5-YL)THIO]-9-[3-(ISOPROPYLAMINO)PROPYL]-9H-PURIN-6-AMINE'>H71</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4z1g|4z1g]], [[4z1h|4z1h]], [[4z1i|4z1i]]</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=4z1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z1f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4z1f RCSB], [http://www.ebi.ac.uk/pdbsum/4z1f PDBsum]</span></td></tr>
+</table>
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.
-The entry 4z1f is ON HOLD
+Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1.,Lee C, Park HK, Jeong H, Lim J, Lee AJ, Cheon KY, Kim CS, Thomas AP, Bae B, Kim ND, Kim SH, Suh PG, Ryu JH, Kang BH J Am Chem Soc. 2015 Apr 8;137(13):4358-67. doi: 10.1021/ja511893n. Epub 2015 Mar , 30. PMID:25785725<ref>PMID:25785725</ref>
-Authors: Lee, C., Park, H.K., Ryu, J.H., Kang, B.H.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Crystal structure of human Trap1 with PU-H71
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Kang, B.H]]
+__TOC__
+</StructureSection>
+[[Category: Kang, B H]]
 [[Category: Lee, C]]
-[[Category: Park, H.K]]
+[[Category: Park, H K]]
-[[Category: Ryu, J.H]]
+[[Category: Ryu, J H]]
+[[Category: Mitochondrial hsp90]]

4z1f

From Proteopedia

Revision as of 12:44, 22 April 2015

Crystal structure of human Trap1 with PU-H71

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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