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2nw4

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[[Image:2nw4.gif|left|200px]]
[[Image:2nw4.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2nw4 |SIZE=350|CAPTION= <scene name='initialview01'>2nw4</scene>, resolution 3.00&Aring;
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The line below this paragraph, containing "STRUCTURE_2nw4", creates the "Structure Box" on the page.
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|SITE=
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|LIGAND= <scene name='pdbligand=8NH:2-CHLORO-4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-3-METHYLBENZONITRILE'>8NH</scene>
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|GENE= Ar, Nr3c4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])
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|DOMAIN=
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{{STRUCTURE_2nw4| PDB=2nw4 | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2nw4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nw4 OCA], [http://www.ebi.ac.uk/pdbsum/2nw4 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2nw4 RCSB]</span>
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'''Crystal Structure of the Rat Androgen Receptor Ligand Binding Domain Complex with BMS-564929'''
'''Crystal Structure of the Rat Androgen Receptor Ligand Binding Domain Complex with BMS-564929'''
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[[Category: Sleph, P G.]]
[[Category: Sleph, P G.]]
[[Category: Sun, C.]]
[[Category: Sun, C.]]
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[[Category: androgen receptor]]
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[[Category: Androgen receptor]]
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[[Category: ligand-binding domain]]
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[[Category: Ligand-binding domain]]
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[[Category: nuclear receptor]]
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[[Category: Nuclear receptor]]
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[[Category: steroid receptor]]
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[[Category: Steroid receptor]]
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[[Category: transcription regulation]]
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[[Category: Transcription regulation]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:58:46 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:09:14 2008''
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Revision as of 06:58, 4 May 2008

Image:2nw4.gif

Template:STRUCTURE 2nw4

Crystal Structure of the Rat Androgen Receptor Ligand Binding Domain Complex with BMS-564929


Overview

A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.

About this Structure

2NW4 is a Single protein structure of sequence from Rattus norvegicus. Full crystallographic information is available from OCA.

Reference

Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats., Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR Jr, Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG, Endocrinology. 2007 Jan;148(1):4-12. Epub 2006 Sep 28. PMID:17008401 Page seeded by OCA on Sun May 4 09:58:46 2008

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