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| | ==Hsp90b N-terminal domain with inhibitors== | | ==Hsp90b N-terminal domain with inhibitors== |
| - | <StructureSection load='5ucj' size='340' side='right' caption='[[5ucj]], [[Resolution|resolution]] 1.69Å' scene=''> | + | <StructureSection load='5ucj' size='340' side='right'caption='[[5ucj]], [[Resolution|resolution]] 1.69Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ucj]] is a 4 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=5UCJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UCJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ucj]] is a 4 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=5UCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UCJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KU3:(5-fluoroisoindolin-2-yl)(4-hydroxy-5-isopropylbenzo[d]isoxazol-7-yl)methanone'>KU3</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]] 1.693Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uch|5uch]], [[5uci|5uci]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KU3:(5-fluoroisoindolin-2-yl)(4-hydroxy-5-isopropylbenzo[d]isoxazol-7-yl)methanone'>KU3</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AB1, HSP90B, HSPC2, HSPCB ([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'>[https://proteopedia.org/fgij/fg.htm?mol=5ucj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ucj OCA], [https://pdbe.org/5ucj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ucj RCSB], [https://www.ebi.ac.uk/pdbsum/5ucj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ucj ProSAT]</span></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=5ucj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ucj OCA], [http://pdbe.org/5ucj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ucj RCSB], [http://www.ebi.ac.uk/pdbsum/5ucj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ucj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HS90B_HUMAN HS90B_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:16478993</ref> <ref>PMID:19696785</ref> | + | [https://www.uniprot.org/uniprot/HS90B_HUMAN HS90B_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:16478993</ref> <ref>PMID:19696785</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5ucj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ucj" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Heat Shock Protein structures|Heat Shock Protein structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Balch, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Deng, J]] | + | [[Category: Balch M]] |
| - | [[Category: Matts, R]] | + | [[Category: Deng J]] |
| - | [[Category: Peng, S]] | + | [[Category: Matts R]] |
| - | [[Category: Chaperone-inhibitor complex]]
| + | [[Category: Peng S]] |
| - | [[Category: Hsp90 inhibitor]]
| + | |
| Structural highlights
Function
HS90B_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.[1] [2]
Publication Abstract from PubMed
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90beta, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90beta-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
Structure-guided design of an Hsp90beta N-terminal isoform-selective inhibitor.,Khandelwal A, Kent CN, Balch M, Peng S, Mishra SJ, Deng J, Day VW, Liu W, Subramanian C, Cohen M, Holzbeierlein JM, Matts R, Blagg BSJ Nat Commun. 2018 Jan 30;9(1):425. doi: 10.1038/s41467-017-02013-1. PMID:29382832[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chadli A, Graham JD, Abel MG, Jackson TA, Gordon DF, Wood WM, Felts SJ, Horwitz KB, Toft D. GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway. Mol Cell Biol. 2006 Mar;26(5):1722-30. PMID:16478993 doi:http://dx.doi.org/26/5/1722
- ↑ Retzlaff M, Stahl M, Eberl HC, Lagleder S, Beck J, Kessler H, Buchner J. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 2009 Oct;10(10):1147-53. Epub 2009 Aug 21. PMID:19696785 doi:http://dx.doi.org/embor2009153
- ↑ Khandelwal A, Kent CN, Balch M, Peng S, Mishra SJ, Deng J, Day VW, Liu W, Subramanian C, Cohen M, Holzbeierlein JM, Matts R, Blagg BSJ. Structure-guided design of an Hsp90beta N-terminal isoform-selective inhibitor. Nat Commun. 2018 Jan 30;9(1):425. doi: 10.1038/s41467-017-02013-1. PMID:29382832 doi:http://dx.doi.org/10.1038/s41467-017-02013-1
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