2xdk

From Proteopedia

(Difference between revisions)

Revision as of 10:50, 13 April 2022

Structure of HSP90 with small molecule inhibitor bound

Structural highlights

2xdk 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:	1yes, 1uy9, 2cdd, 1byq, 2bsm, 1osf, 2wi3, 1uy8, 2bug, 2wi4, 2uwd, 2wi7, 2bt0, 1yer, 1uyg, 2ccu, 2bz5, 2ccs, 1yc3, 1uyi, 1uyf, 1uyd, 2byi, 2wi2, 2vci, 1uy6, 2wi1, 2vcj, 1yc4, 2fwz, 2c2l, 1uyk, 1uyh, 2cct, 2fwy, 1uye, 1uyl, 2wi6, 2xab, 1yc1, 1uy7, 1uyc, 1yet, 2jjc, 2byh, 2wi5, 2xdl
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 chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.

Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency.,Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493^[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
↑ Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ. Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493 doi:10.1021/jm100059d

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/2xdk"

@@ Line 3: / Line 3: @@
 <StructureSection load='2xdk' size='340' side='right'caption='[[2xdk]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xdk]] 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=2XDK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2XDK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xdk]] 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=2XDK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XDK FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XDK:2-AMINO-4-PYRIDYL-PYRIMIDINE'>XDK</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1yes|1yes]], [[1uy9|1uy9]], [[2cdd|2cdd]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2bz5|2bz5]], [[2ccs|2ccs]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyf|1uyf]], [[1uyd|1uyd]], [[2byi|2byi]], [[2wi2|2wi2]], [[2vci|2vci]], [[1uy6|1uy6]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2fwz|2fwz]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[1uyh|1uyh]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uye|1uye]], [[1uyl|1uyl]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[1uy7|1uy7]], [[1uyc|1uyc]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]], [[2xdl|2xdl]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1yes|1yes]], [[1uy9|1uy9]], [[2cdd|2cdd]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2bz5|2bz5]], [[2ccs|2ccs]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyf|1uyf]], [[1uyd|1uyd]], [[2byi|2byi]], [[2wi2|2wi2]], [[2vci|2vci]], [[1uy6|1uy6]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2fwz|2fwz]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[1uyh|1uyh]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uye|1uye]], [[1uyl|1uyl]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[1uy7|1uy7]], [[1uyc|1uyc]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]], [[2xdl|2xdl]]</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=2xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xdk OCA], [http://pdbe.org/2xdk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xdk RCSB], [http://www.ebi.ac.uk/pdbsum/2xdk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xdk 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=2xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xdk OCA], [https://pdbe.org/2xdk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xdk RCSB], [https://www.ebi.ac.uk/pdbsum/2xdk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xdk 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]]

2xdk

From Proteopedia

Revision as of 10:50, 13 April 2022

Structure of HSP90 with small molecule inhibitor bound

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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