3wha

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{{STRUCTURE_3wha| PDB=3wha | SCENE= }}
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==Hsp90 alpha N-terminal domain in complex with a tricyclic inhibitor==
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===Hsp90 alpha N-terminal domain in complex with a tricyclic inhibitor===
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<StructureSection load='3wha' size='340' side='right' caption='[[3wha]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24369839}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3wha]] is a 2 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=3WHA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WHA FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=WHA:4-{[4-AMINO-6-(5-CHLORO-1H,3H-BENZO[DE]ISOCHROMEN-6-YL)-1,3,5-TRIAZIN-2-YL]SULFANYL}BUTANAMIDE'>WHA</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b28|3b28]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<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=3wha FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wha OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wha RCSB], [http://www.ebi.ac.uk/pdbsum/3wha PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90alpha (Kd=0.52nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50=0.098muM, NCI-N87 IC50=0.066muM) and also displayed high oral bioavailability in mice (F=44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition=136%).
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==Function==
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Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.,Suda A, Kawasaki K, Komiyama S, Isshiki Y, Yoon DO, Kim SJ, Na YJ, Hasegawa K, Fukami TA, Sato S, Miura T, Ono N, Yamazaki T, Saitoh R, Shimma N, Shiratori Y, Tsukuda T Bioorg Med Chem. 2014 Jan 15;22(2):892-905. doi: 10.1016/j.bmc.2013.11.036. Epub , 2013 Nov 25. PMID:24369839<ref>PMID:24369839</ref>
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[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3wha]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WHA OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:024369839</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: Fukami, T A.]]
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</StructureSection>
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[[Category: Ono, N.]]
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[[Category: Human]]
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[[Category: Fukami, T A]]
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[[Category: Ono, N]]
[[Category: Chaperone]]
[[Category: Chaperone]]
[[Category: Chaperone-chaperone inhibitor complex]]
[[Category: Chaperone-chaperone inhibitor complex]]

Revision as of 16:51, 21 December 2014

Hsp90 alpha N-terminal domain in complex with a tricyclic inhibitor

3wha, resolution 1.30Å

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