2uwd

From Proteopedia

(Difference between revisions)

Current revision

Inhibition of the HSP90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole, isoxazole amide analogs

Structural highlights

2uwd 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 1.9Å
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

Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.,Sharp SY, Prodromou C, Boxall K, Powers MV, Holmes JL, Box G, Matthews TP, Cheung KM, Kalusa A, James K, Hayes A, Hardcastle A, Dymock B, Brough PA, Barril X, Cansfield JE, Wright L, Surgenor A, Foloppe N, Hubbard RE, Aherne W, Pearl L, Jones K, McDonald E, Raynaud F, Eccles S, Drysdale M, Workman P Mol Cancer Ther. 2007 Apr;6(4):1198-211. PMID:17431102^[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
↑ Sharp SY, Prodromou C, Boxall K, Powers MV, Holmes JL, Box G, Matthews TP, Cheung KM, Kalusa A, James K, Hayes A, Hardcastle A, Dymock B, Brough PA, Barril X, Cansfield JE, Wright L, Surgenor A, Foloppe N, Hubbard RE, Aherne W, Pearl L, Jones K, McDonald E, Raynaud F, Eccles S, Drysdale M, Workman P. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther. 2007 Apr;6(4):1198-211. PMID:17431102 doi:6/4/1198

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/2uwd"

@@ Line 1: / Line 1: @@
-==INHIBITION OF THE HSP90 MOLECULAR CHAPERONE IN VITRO AND IN VIVO BY NOVEL, SYNTHETIC, POTENT RESORCINYLIC PYRAZOLE, ISOXAZOLE AMIDE ANALOGS==
+==Inhibition of the HSP90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole, isoxazole amide analogs==
-<StructureSection load='2uwd' size='340' side='right' caption='[[2uwd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='2uwd' size='340' side='right'caption='[[2uwd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2uwd]] 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=2UWD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2UWD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2uwd]] 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=2UWD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2UWD FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2GG:5-(5-CHLORO-2,4-DIHYDROXYPHENYL)-N-ETHYL-4-(4-METHOXYPHENYL)ISOXAZOLE-3-CARBOXAMIDE'>2GG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.9&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1byq|1byq]], [[1osf|1osf]], [[1uy6|1uy6]], [[1uy7|1uy7]], [[1uy8|1uy8]], [[1uy9|1uy9]], [[1uyc|1uyc]], [[1uyd|1uyd]], [[1uye|1uye]], [[1uyf|1uyf]], [[1uyg|1uyg]], [[1uyh|1uyh]], [[1uyi|1uyi]], [[1uyk|1uyk]], [[1uyl|1uyl]], [[1yc1|1yc1]], [[1yc3|1yc3]], [[1yc4|1yc4]], [[1yer|1yer]], [[1yes|1yes]], [[1yet|1yet]], [[2bsm|2bsm]], [[2bt0|2bt0]], [[2bug|2bug]], [[2byh|2byh]], [[2byi|2byi]], [[2bz5|2bz5]], [[2c2l|2c2l]], [[2ccs|2ccs]], [[2cct|2cct]], [[2ccu|2ccu]], [[2cdd|2cdd]], [[2fwy|2fwy]], [[2fwz|2fwz]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2GG:5-(5-CHLORO-2,4-DIHYDROXYPHENYL)-N-ETHYL-4-(4-METHOXYPHENYL)ISOXAZOLE-3-CARBOXAMIDE'>2GG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2uwd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uwd OCA], [http://pdbe.org/2uwd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2uwd RCSB], [http://www.ebi.ac.uk/pdbsum/2uwd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2uwd 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=2uwd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uwd OCA], [https://pdbe.org/2uwd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2uwd RCSB], [https://www.ebi.ac.uk/pdbsum/2uwd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2uwd 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/uw/2uwd_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/uw/2uwd_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 29: / Line 31: @@
 ==See Also==
-*[[Heat Shock Proteins|Heat Shock Proteins]]
+*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Aherne, W]]
+[[Category: Large Structures]]
-[[Category: Barril, X]]
+[[Category: Aherne W]]
-[[Category: Box, G]]
+[[Category: Barril X]]
-[[Category: Boxall, K]]
+[[Category: Box G]]
-[[Category: Brough, P A]]
+[[Category: Boxall K]]
-[[Category: Cansfield, J E]]
+[[Category: Brough PA]]
-[[Category: Cheung, K M]]
+[[Category: Cansfield JE]]
-[[Category: Drysdale, M]]
+[[Category: Cheung KM]]
-[[Category: Dymock, B]]
+[[Category: Drysdale M]]
-[[Category: Eccles, S]]
+[[Category: Dymock B]]
-[[Category: Foloppe, N]]
+[[Category: Eccles S]]
-[[Category: Hardcastle, A]]
+[[Category: Foloppe N]]
-[[Category: Hayes, A]]
+[[Category: Hardcastle A]]
-[[Category: Holmes, J L]]
+[[Category: Hayes A]]
-[[Category: James, K]]
+[[Category: Holmes JL]]
-[[Category: Jones, K]]
+[[Category: James K]]
-[[Category: Kalusa, A]]
+[[Category: Jones K]]
-[[Category: Matthews, T P]]
+[[Category: Kalusa A]]
-[[Category: Mcdonald, E]]
+[[Category: Matthews TP]]
-[[Category: Pearl, L]]
+[[Category: McDonald E]]
-[[Category: Powers, M V]]
+[[Category: Pearl L]]
-[[Category: Prodromou, C]]
+[[Category: Powers MV]]
-[[Category: Raynaud, F]]
+[[Category: Prodromou C]]
-[[Category: Sharp, S Y]]
+[[Category: Raynaud F]]
-[[Category: Surgenor, A]]
+[[Category: Sharp SY]]
-[[Category: Workman, P]]
+[[Category: Surgenor A]]
-[[Category: Wright, L M]]
+[[Category: Workman P]]
-[[Category: Atp-binding]]
+[[Category: Wright LM]]
-[[Category: Chaperone]]
-[[Category: Heat shock]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphorylation]]

2uwd

From Proteopedia

Current revision

Inhibition of the HSP90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole, isoxazole amide analogs

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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