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7c7b

From Proteopedia

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Current revision

Crystal structure of human TRAP1 with SJT009

Structural highlights

7c7b is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.5Å
Ligands:
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

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is overexpressed in the mitochondria of various cancer cells, reprograms cellular metabolism to enable cancer cells to adapt to harsh tumor environments. As inactivation of TRAP1 induces massive apoptosis in cancer cells in vitro and in vivo, the development of TRAP1-selective inhibitors has become an attractive approach. A series of purine-8-one and pyrrolo[2,3-d]pyrimidine derivatives was developed based on TRAP1 structure and identified to be highly selective in vitro for TRAP1 over the paralogous enzymes, Hsp90alpha and Grp94. The TRAP1-selective inhibition strategy via utilization of the Asn171 residue of the ATP-lid was investigated using X-ray crystallography and molecular dynamics simulation studies. Among various synthesized potent TRAP1 inhibitors, 5f possessed a 65-fold selectivity over Hsp90alpha and a 13-fold selectivity over Grp94. Additionally, 6f had a half-maximal inhibitory concentration (IC50) of 63.5 nM for TRAP1, with a 78-fold and 30-fold selectivity over Hsp90alpha and Grp94, respectively.

Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity.,Yang S, Yoon NG, Kim D, Park E, Kim SY, Lee JH, Lee C, Kang BH, Kang S ACS Med Chem Lett. 2021 Jun 16;12(7):1173-1180. doi:, 10.1021/acsmedchemlett.1c00213. eCollection 2021 Jul 8. PMID:34267888^[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
↑ Yang S, Yoon NG, Kim D, Park E, Kim SY, Lee JH, Lee C, Kang BH, Kang S. Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity. ACS Med Chem Lett. 2021 Jun 16;12(7):1173-1180. doi:, 10.1021/acsmedchemlett.1c00213. eCollection 2021 Jul 8. PMID:34267888 doi:http://dx.doi.org/10.1021/acsmedchemlett.1c00213

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7c7b"

@@ Line 3: / Line 3: @@
 <StructureSection load='7c7b' size='340' side='right'caption='[[7c7b]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7c7b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C7B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7c7b]] 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=7C7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C7B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FJX:2-azanyl-9-[(6-bromanyl-1,3-benzodioxol-5-yl)methyl]-6-chloranyl-purin-8-ol'>FJX</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]] 1.5&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRAP1, HSP75 ([https://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=FJX:2-azanyl-9-[(6-bromanyl-1,3-benzodioxol-5-yl)methyl]-6-chloranyl-purin-8-ol'>FJX</scene></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=7c7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c7b OCA], [https://pdbe.org/7c7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c7b RCSB], [https://www.ebi.ac.uk/pdbsum/7c7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c7b ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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 ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Kang, B H]]
+[[Category: Kang BH]]
-[[Category: Kang, S]]
+[[Category: Kang S]]
-[[Category: Kim, D]]
+[[Category: Kim D]]
-[[Category: Kim, S Y]]
+[[Category: Kim SY]]
-[[Category: Lee, C]]
+[[Category: Lee C]]
-[[Category: Park, E]]
+[[Category: Park E]]
-[[Category: Yang, S]]
+[[Category: Yang S]]
-[[Category: Yoon, N G]]
+[[Category: Yoon NG]]
-[[Category: Anticancer]]
-[[Category: Chaperone]]
-[[Category: Drug]]
-[[Category: Hsp90]]
-[[Category: Mitochondria]]
-[[Category: Selectivity]]
-[[Category: Trap1]]

7c7b

From Proteopedia

Current revision

Crystal structure of human TRAP1 with SJT009

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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