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[[Image:2bt0.gif|left|200px]]
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{{STRUCTURE_2bt0|  PDB=2bt0  |  SCENE=  }}
'''NOVEL, POTENT SMALL MOLECULE INHIBITORS OF THE MOLECULAR CHAPERONE HSP90 DISCOVERED THROUGH STRUCTURE-BASED DESIGN'''


==Novel, potent small molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design==
<StructureSection load='2bt0' size='340' side='right'caption='[[2bt0]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2bt0]] is a 2 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=2BT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BT0 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CT5:4-[4-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YL)-3-METHYL-1H-PYRAZOL-5-YL]-6-ETHYLBENZENE-1,3-DIOL'>CT5</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=2bt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bt0 OCA], [https://pdbe.org/2bt0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bt0 RCSB], [https://www.ebi.ac.uk/pdbsum/2bt0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bt0 ProSAT]</span></td></tr>
</table>
== Function ==
[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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bt/2bt0_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bt0 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.


==Overview==
Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.,Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ J Med Chem. 2005 Jun 30;48(13):4212-5. PMID:15974572<ref>PMID:15974572</ref>
The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2BT0 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BT0 OCA].
</div>
<div class="pdbe-citations 2bt0" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design., Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ, J Med Chem. 2005 Jun 30;48(13):4212-5. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15974572 15974572]
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Barril, X.]]
[[Category: Barril X]]
[[Category: Brough, P A.]]
[[Category: Brough PA]]
[[Category: Cansfield, J E.]]
[[Category: Cansfield JE]]
[[Category: Drysdale, M J.]]
[[Category: Drysdale MJ]]
[[Category: Dymock, B W.]]
[[Category: Dymock BW]]
[[Category: Hubbard, R E.]]
[[Category: Hubbard RE]]
[[Category: Massey, A.]]
[[Category: Massey A]]
[[Category: Mcdonald, E.]]
[[Category: McDonald E]]
[[Category: Roughley, S D.]]
[[Category: Roughley SD]]
[[Category: Surgenor, A.]]
[[Category: Surgenor A]]
[[Category: Webb, P.]]
[[Category: Webb P]]
[[Category: Workman, P.]]
[[Category: Workman P]]
[[Category: Wright, L.]]
[[Category: Wright L]]
[[Category: Atp-binding]]
[[Category: Chaperone]]
[[Category: Heat shock]]
[[Category: Phosphorylation]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 20:45:29 2008''

Latest revision as of 16:55, 13 December 2023

Novel, potent small molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based designNovel, potent small molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design

Structural highlights

2bt0 is a 2 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 1.9Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.,Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ J Med Chem. 2005 Jun 30;48(13):4212-5. PMID:15974572[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem. 2005 Jun 30;48(13):4212-5. PMID:15974572 doi:10.1021/jm050355z

2bt0, resolution 1.90Å

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