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| | ==Candida albicans Hsp90 nucleotide binding domain in complex with ADP== | | ==Candida albicans Hsp90 nucleotide binding domain in complex with ADP== |
| - | <StructureSection load='6cjj' size='340' side='right' caption='[[6cjj]], [[Resolution|resolution]] 1.74Å' scene=''> | + | <StructureSection load='6cjj' size='340' side='right'caption='[[6cjj]], [[Resolution|resolution]] 1.74Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cjj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Canal Canal]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CJJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CJJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cjj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans_SC5314 Candida albicans SC5314]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CJJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.74Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6cji|6cji]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90, CAALFM_C702030WA, CaJ7.0234, CaO19.13868, CaO19.6515 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=237561 CANAL])</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=6cjj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cjj OCA], [https://pdbe.org/6cjj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cjj RCSB], [https://www.ebi.ac.uk/pdbsum/6cjj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cjj 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=6cjj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cjj OCA], [http://pdbe.org/6cjj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cjj RCSB], [http://www.ebi.ac.uk/pdbsum/6cjj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cjj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HSP90_CANAL HSP90_CANAL]] 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 (By similarity). | + | [https://www.uniprot.org/uniprot/HSP90_CANAL HSP90_CANAL] 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 (By similarity). |
| | <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 6cjj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cjj" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Heat Shock Protein structures|Heat Shock Protein structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Canal]] | + | [[Category: Candida albicans SC5314]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Large Structures]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arrowsmith CH]] |
| | + | [[Category: Bountra C]] |
| | + | [[Category: Edwards AM]] |
| | + | [[Category: Hui R]] |
| | + | [[Category: Hutchinson A]] |
| | + | [[Category: Loppnau P]] |
| | + | [[Category: Pizarro JC]] |
| | [[Category: Structural genomic]] | | [[Category: Structural genomic]] |
| - | [[Category: Edwards, A M]] | |
| - | [[Category: Hui, R]] | |
| - | [[Category: Hutchinson, A]] | |
| - | [[Category: Loppnau, P]] | |
| - | [[Category: Pizarro, J C]] | |
| - | [[Category: Chaperone]] | |
| - | [[Category: Hsp90. atpase]] | |
| - | [[Category: Sgc]] | |
| Structural highlights
Function
HSP90_CANAL 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 (By similarity).
Publication Abstract from PubMed
New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans. Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe's species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy.
Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus.,Whitesell L, Robbins N, Huang DS, McLellan CA, Shekhar-Guturja T, LeBlanc EV, Nation CS, Hui R, Hutchinson A, Collins C, Chatterjee S, Trilles R, Xie JL, Krysan DJ, Lindquist S, Porco JA Jr, Tatu U, Brown LE, Pizarro J, Cowen LE Nat Commun. 2019 Jan 24;10(1):402. doi: 10.1038/s41467-018-08248-w. PMID:30679438[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Whitesell L, Robbins N, Huang DS, McLellan CA, Shekhar-Guturja T, LeBlanc EV, Nation CS, Hui R, Hutchinson A, Collins C, Chatterjee S, Trilles R, Xie JL, Krysan DJ, Lindquist S, Porco JA Jr, Tatu U, Brown LE, Pizarro J, Cowen LE. Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus. Nat Commun. 2019 Jan 24;10(1):402. doi: 10.1038/s41467-018-08248-w. PMID:30679438 doi:http://dx.doi.org/10.1038/s41467-018-08248-w
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