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| | <StructureSection load='5fnc' size='340' side='right'caption='[[5fnc]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='5fnc' size='340' side='right'caption='[[5fnc]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fnc]] is a 1 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=5FNC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FNC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fnc]] 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=5FNC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FNC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IEE:6-CHLORO-4-N-[(4-METHYLPHENYL)METHYL]PYRIMIDINE-+2,4-DIAMINE'>IEE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5fnd|5fnd]], [[5fnf|5fnf]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IEE:6-CHLORO-4-N-[(4-METHYLPHENYL)METHYL]PYRIMIDINE-+2,4-DIAMINE'>IEE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5fnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fnc OCA], [http://pdbe.org/5fnc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fnc RCSB], [http://www.ebi.ac.uk/pdbsum/5fnc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fnc ProSAT]</span></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=5fnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fnc OCA], [https://pdbe.org/5fnc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fnc RCSB], [https://www.ebi.ac.uk/pdbsum/5fnc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fnc ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> | + | [https://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Baker, L M]] | + | [[Category: Baker LM]] |
| - | [[Category: Barril, X]] | + | [[Category: Barril X]] |
| - | [[Category: Davis, B]] | + | [[Category: Davis B]] |
| - | [[Category: Hubbard, R]] | + | [[Category: Hubbard R]] |
| - | [[Category: Luque, F J]] | + | [[Category: Luque FJ]] |
| - | [[Category: Matassova, N]] | + | [[Category: Matassova N]] |
| - | [[Category: Murray, J]] | + | [[Category: Murray J]] |
| - | [[Category: Roughley, S]] | + | [[Category: Roughley S]] |
| - | [[Category: Ruiz-Carmona, S]] | + | [[Category: Ruiz-Carmona S]] |
| - | [[Category: Schmidtke, P]] | + | [[Category: Schmidtke P]] |
| - | [[Category: Chaperone]]
| + | |
| - | [[Category: Drug design]]
| + | |
| - | [[Category: Hsp90]]
| + | |
| - | [[Category: Oncology]]
| + | |
| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other 'thermodynamic' methods. We demonstrate the potential of the docking-undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%.
Dynamic undocking and the quasi-bound state as tools for drug discovery.,Ruiz-Carmona S, Schmidtke P, Luque FJ, Baker L, Matassova N, Davis B, Roughley S, Murray J, Hubbard R, Barril X Nat Chem. 2017 Mar;9(3):201-206. doi: 10.1038/nchem.2660. Epub 2016 Nov 14. PMID:28221352[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
- ↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
- ↑ Ruiz-Carmona S, Schmidtke P, Luque FJ, Baker L, Matassova N, Davis B, Roughley S, Murray J, Hubbard R, Barril X. Dynamic undocking and the quasi-bound state as tools for drug discovery. Nat Chem. 2017 Mar;9(3):201-206. doi: 10.1038/nchem.2660. Epub 2016 Nov 14. PMID:28221352 doi:http://dx.doi.org/10.1038/nchem.2660
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