2xjx

From Proteopedia

(Difference between revisions)

Revision as of 10:54, 13 April 2022

Structure of HSP90 with small molecule inhibitor bound

Structural highlights

2xjx is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2cdd, 1yes, 1uy9, 1byq, 2bsm, 1osf, 2wi3, 1uy8, 2bug, 2wi4, 2uwd, 2xhx, 2wi7, 2bt0, 1yer, 2xdu, 1uyg, 2bz5, 2ccu, 2xds, 2xdx, 2ccs, 1uyf, 1yc3, 1uyi, 1uyd, 2byi, 2xdl, 2wi2, 1uy6, 2vci, 2wi1, 2vcj, 1yc4, 2c2l, 2fwz, 2xdk, 1uyh, 2xjg, 1uyk, 2cct, 2fwy, 1uyl, 1uye, 2wi6, 2xab, 1yc1, 2xhr, 1uyc, 2xht, 1uy7, 1yet, 2jjc, 2byh, 2wi5, 2xjj
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

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design.,Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ J Med Chem. 2010 Jul 28. PMID:20662534^[3]

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

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
↑ Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ. Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design. J Med Chem. 2010 Jul 28. PMID:20662534 doi:10.1021/jm100060b

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xjx"

@@ Line 3: / Line 3: @@
 <StructureSection load='2xjx' size='340' side='right'caption='[[2xjx]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xjx]] 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=2XJX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2XJX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xjx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XJX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XJX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XJX:ONALESPIB'>XJX</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2cdd|2cdd]], [[1yes|1yes]], [[1uy9|1uy9]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2xhx|2xhx]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2bz5|2bz5]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyd|1uyd]], [[2byi|2byi]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[1uy6|1uy6]], [[2vci|2vci]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2c2l|2c2l]], [[2fwz|2fwz]], [[2xdk|2xdk]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[1uyk|1uyk]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[2xhr|2xhr]], [[1uyc|1uyc]], [[2xht|2xht]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]], [[2xjj|2xjj]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2cdd|2cdd]], [[1yes|1yes]], [[1uy9|1uy9]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2xhx|2xhx]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2bz5|2bz5]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyd|1uyd]], [[2byi|2byi]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[1uy6|1uy6]], [[2vci|2vci]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2c2l|2c2l]], [[2fwz|2fwz]], [[2xdk|2xdk]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[1uyk|1uyk]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[2xhr|2xhr]], [[1uyc|1uyc]], [[2xht|2xht]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]], [[2xjj|2xjj]]</div></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2xjx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xjx OCA], [http://pdbe.org/2xjx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xjx RCSB], [http://www.ebi.ac.uk/pdbsum/2xjx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xjx 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=2xjx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xjx OCA], [https://pdbe.org/2xjx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xjx RCSB], [https://www.ebi.ac.uk/pdbsum/2xjx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xjx ProSAT]</span></td></tr>
 </table>
 == 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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]

2xjx

From Proteopedia

Revision as of 10:54, 13 April 2022

Structure of HSP90 with small molecule inhibitor bound

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

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