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2pit

From Proteopedia

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{{STRUCTURE_2pit| PDB=2pit | SCENE= }}
{{STRUCTURE_2pit| PDB=2pit | SCENE= }}
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'''Androgen receptor LBD with small molecule'''
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===Androgen receptor LBD with small molecule===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_17911242}}
==About this Structure==
==About this Structure==
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[[Category: Androgen receptor coactivator binding inhibitors af-2]]
[[Category: Androgen receptor coactivator binding inhibitors af-2]]
[[Category: Hormone receptor]]
[[Category: Hormone receptor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May 28 09:31:10 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:15:55 2008''

Revision as of 08:15, 28 July 2008

Image:2pit.png

Template:STRUCTURE 2pit

Androgen receptor LBD with small molecule

Template:ABSTRACT PUBMED 17911242

About this Structure

2PIT is a Single protein structure of sequence from Homo sapiens. 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 Jul 28 11:15:55 2008

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