7c05

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human Trap1 with DN203495

Structural highlights

7c05 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 2.59Å
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

TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.

Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models.,Kim D, Kim SY, Kim D, Yoon NG, Yun J, Hong KB, Lee C, Lee JH, Kang BH, Kang S Bioorg Chem. 2020 Jun 15;101:103901. doi: 10.1016/j.bioorg.2020.103901. PMID:32590225^[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
↑ Kim D, Kim SY, Kim D, Yoon NG, Yun J, Hong KB, Lee C, Lee JH, Kang BH, Kang S. Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models. Bioorg Chem. 2020 Aug;101:103901. PMID:32590225 doi:10.1016/j.bioorg.2020.103901

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/7c05"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7c05 is ON HOLD
+==Crystal structure of human Trap1 with DN203495==
+<StructureSection load='7c05' size='340' side='right'caption='[[7c05]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7c05]] 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=7C05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C05 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE6:1-[(4-bromanyl-2-fluoranyl-phenyl)methyl]-4-chloranyl-pyrazolo[3,4-d]pyrimidin-6-amine'>FE6</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=7c05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c05 OCA], [https://pdbe.org/7c05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c05 RCSB], [https://www.ebi.ac.uk/pdbsum/7c05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c05 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.
-Authors: Kim, D., Kim, D., Kim, S.Y., Lee, J.H., Kang, B.H., Kang, S., Lee, C.
+Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models.,Kim D, Kim SY, Kim D, Yoon NG, Yun J, Hong KB, Lee C, Lee JH, Kang BH, Kang S Bioorg Chem. 2020 Jun 15;101:103901. doi: 10.1016/j.bioorg.2020.103901. PMID:32590225<ref>PMID:32590225</ref>
-Description: Crystal structure of human Trap1 with DN203495
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lee, J.H]]
+<div class="pdbe-citations 7c05" style="background-color:#fffaf0;"></div>
-[[Category: Kang, B.H]]
-[[Category: Lee, C]]
+==See Also==
-[[Category: Kim, S.Y]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
-[[Category: Kang, S]]
+== References ==
-[[Category: Kim, D]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kang BH]]
+[[Category: Kang S]]
+[[Category: Kim D]]
+[[Category: Kim SY]]
+[[Category: Lee C]]
+[[Category: Lee JH]]

7c05

From Proteopedia

Current revision

Crystal structure of human Trap1 with DN203495

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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