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==Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors==
==Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors==
<StructureSection load='4xir' size='340' side='right' caption='[[4xir]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
<StructureSection load='4xir' size='340' side='right'caption='[[4xir]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4xir]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XIR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XIR FirstGlance]. <br>
<table><tr><td colspan='2'>[[4xir]] 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=4XIR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XIR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40X:(6S)-2-CHLORO-8,11,11-TRIMETHYL-9-OXO-6-PROPYL-6,7,9,10,11,12-HEXAHYDROINDOLO[2,1-D][1,5]BENZOXAZEPINE-3-CARBOXAMIDE'>40X</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xip|4xip]], [[4xiq|4xiq]], [[4xit|4xit]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=40X:(6S)-2-CHLORO-8,11,11-TRIMETHYL-9-OXO-6-PROPYL-6,7,9,10,11,12-HEXAHYDROINDOLO[2,1-D][1,5]BENZOXAZEPINE-3-CARBOXAMIDE'>40X</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xir FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xir OCA], [http://pdbe.org/4xir PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xir RCSB], [http://www.ebi.ac.uk/pdbsum/4xir PDBsum]</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=4xir FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xir OCA], [https://pdbe.org/4xir PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xir RCSB], [https://www.ebi.ac.uk/pdbsum/4xir PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xir 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;">
== Publication Abstract from PubMed ==
Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).
 
Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.,Neubert T, Numa M, Ernst J, Clemens J, Krenitsky P, Liu M, Fleck B, Woody L, Zuccola H, Stamos D Bioorg Med Chem Lett. 2015 Mar 15;25(6):1338-42. doi: 10.1016/j.bmcl.2015.01.023., Epub 2015 Jan 20. PMID:25677667<ref>PMID:25677667</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4xir" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Heat Shock Proteins|Heat Shock Proteins]]
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Neubert, T]]
[[Category: Homo sapiens]]
[[Category: Zuccola, H J]]
[[Category: Large Structures]]
[[Category: Chaperone-chaperone inhibitor complex]]
[[Category: Neubert T]]
[[Category: Zuccola HJ]]

Latest revision as of 16:01, 1 March 2024

Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitorsDiscovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors

Structural highlights

4xir is a 1 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 1.7Å
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]

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

4xir, resolution 1.70Å

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