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2fwz
From Proteopedia
| Line 7: | Line 7: | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1zw9|1ZW9]], [[1uy6|1UY6]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fwz OCA], [http://www.ebi.ac.uk/pdbsum/2fwz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2fwz RCSB]</span> | ||
}} | }} | ||
| Line 24: | Line 27: | ||
[[Category: Gewirth, D T.]] | [[Category: Gewirth, D T.]] | ||
[[Category: Immormino, R M.]] | [[Category: Immormino, R M.]] | ||
| - | [[Category: H71]] | ||
[[Category: chaperone]] | [[Category: chaperone]] | ||
[[Category: grp94]] | [[Category: grp94]] | ||
| Line 33: | Line 35: | ||
[[Category: purine]] | [[Category: purine]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:08:51 2008'' |
Revision as of 00:08, 31 March 2008
| |||||||
| , resolution 2.10Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | HSPCA (Homo sapiens) | ||||||
| Related: | 1ZW9, 1UY6
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H71
Overview
Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are an attractive target for anti-cancer therapeutics. We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90alpha. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2'-halide of the 8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2'-halide is rotated approximately 180 degrees away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2'-halo derivatives of the 3',4',5'-trimethoxy series where Cl > Br > I compared to the 4',5'-methylenedioxy series where I > Br > Cl. We also present quantum chemical calculations of 2 and its analogues that illuminate their basis for Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observed conformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold.
About this Structure
2FWZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors., Immormino RM, Kang Y, Chiosis G, Gewirth DT, J Med Chem. 2006 Aug 10;49(16):4953-60. PMID:16884307
Page seeded by OCA on Mon Mar 31 03:08:51 2008
Categories: Homo sapiens | Single protein | Gewirth, D T. | Immormino, R M. | Chaperone | Grp94 | H64 | H71 | Hsp90 | Pu3 | Purine
