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< | ==STRUCTURE OF THE HSP90 INHIBITOR MACBECIN BOUND TO THE N-TERMINUS OF YEAST HSP90.== | ||
<StructureSection load='2vwc' size='340' side='right'caption='[[2vwc]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vwc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2vls 2vls]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VWC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VWC 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]] 2.4Å</td></tr> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BC2:MACBECIN'>BC2</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=2vwc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vwc OCA], [https://pdbe.org/2vwc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vwc RCSB], [https://www.ebi.ac.uk/pdbsum/2vwc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vwc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HSP82_YEAST HSP82_YEAST] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.<ref>PMID:17114002</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/vw/2vwc_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=2vwc ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC 50 = 2 microM) and binding with higher affinity ( K d = 0.24 microM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/ C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization. | |||
Molecular Characterization of Macbecin as an Hsp90 Inhibitor.,Martin CJ, Gaisser S, Challis IR, Carletti I, Wilkinson B, Gregory M, Prodromou C, Roe SM, Pearl LH, Boyd SM, Zhang MQ J Med Chem. 2008 Mar 22;. PMID:18357975<ref>PMID:18357975</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2vwc" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Heat Shock Protein structures|Heat Shock Protein structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[Category: Saccharomyces cerevisiae]] | [[Category: Saccharomyces cerevisiae]] | ||
[[Category: Pearl LH]] | |||
[[Category: Pearl | [[Category: Prodromou C]] | ||
[[Category: Prodromou | [[Category: Roe SM]] | ||
[[Category: Roe | |||
Latest revision as of 18:34, 13 December 2023
STRUCTURE OF THE HSP90 INHIBITOR MACBECIN BOUND TO THE N-TERMINUS OF YEAST HSP90.STRUCTURE OF THE HSP90 INHIBITOR MACBECIN BOUND TO THE N-TERMINUS OF YEAST HSP90.
Structural highlights
FunctionHSP82_YEAST Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.[1] 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 PubMedMacbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC 50 = 2 microM) and binding with higher affinity ( K d = 0.24 microM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/ C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization. Molecular Characterization of Macbecin as an Hsp90 Inhibitor.,Martin CJ, Gaisser S, Challis IR, Carletti I, Wilkinson B, Gregory M, Prodromou C, Roe SM, Pearl LH, Boyd SM, Zhang MQ J Med Chem. 2008 Mar 22;. PMID:18357975[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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