2qpy
From Proteopedia
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|PDB= 2qpy |SIZE=350|CAPTION= <scene name='initialview01'>2qpy</scene>, resolution 2.5Å | |PDB= 2qpy |SIZE=350|CAPTION= <scene name='initialview01'>2qpy</scene>, resolution 2.5Å | ||
|SITE= <scene name='pdbsite=AC1:Dht+Binding+Site+For+Residue+A+931'>AC1</scene> and <scene name='pdbsite=AC2:4hy+Binding+Site+For+Residue+A+1'>AC2</scene> | |SITE= <scene name='pdbsite=AC1:Dht+Binding+Site+For+Residue+A+931'>AC1</scene> and <scene name='pdbsite=AC2:4hy+Binding+Site+For+Residue+A+1'>AC2</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene>, <scene name='pdbligand=DHT:DIHYDROTESTOSTERONE'>DHT</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= Ar, Nr3c4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus]) | |GENE= Ar, Nr3c4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qpy OCA], [http://www.ebi.ac.uk/pdbsum/2qpy PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qpy RCSB]</span> | ||
}} | }} | ||
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[[Category: Estebanez-Perpina, E.]] | [[Category: Estebanez-Perpina, E.]] | ||
[[Category: Fletterick, R.]] | [[Category: Fletterick, R.]] | ||
| - | [[Category: 4HY]] | ||
| - | [[Category: DHT]] | ||
[[Category: androgen receptor dht coactivator]] | [[Category: androgen receptor dht coactivator]] | ||
[[Category: dna binding protein]] | [[Category: dna binding protein]] | ||
| Line 39: | Line 40: | ||
[[Category: zinc-finger]] | [[Category: zinc-finger]] | ||
| - | ''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 04:51:56 2008'' |
Revision as of 01:52, 31 March 2008
| |||||||
| , resolution 2.5Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | and | ||||||
| Ligands: | , | ||||||
| Gene: | Ar, Nr3c4 (Mus musculus) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
AR LBD with small molecule
Overview
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
About this Structure
2QPY is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.
Reference
A surface on the androgen receptor that allosterically regulates coactivator binding., Estebanez-Perpina E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ, Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16074-9. Epub 2007 Oct 2. PMID:17911242
Page seeded by OCA on Mon Mar 31 04:51:56 2008
