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| - | [[Image:2ihq.jpg|left|200px]] | |
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| - | <!--
| + | ==Crystal Structure of the Rat Androgen Receptor Ligand Binding Domian Complex with an N-Aryl-Hydroxybicyclohydantoin== |
| - | The line below this paragraph, containing "STRUCTURE_2ihq", creates the "Structure Box" on the page.
| + | <StructureSection load='2ihq' size='340' side='right'caption='[[2ihq]], [[Resolution|resolution]] 2.00Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[2ihq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IHQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IHQ FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LG7:4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILE'>LG7</scene></td></tr> |
| - | {{STRUCTURE_2ihq| PDB=2ihq | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ihq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ihq OCA], [https://pdbe.org/2ihq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ihq RCSB], [https://www.ebi.ac.uk/pdbsum/2ihq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ihq ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ANDR_RAT ANDR_RAT] Note=Defects in Ar are a cause of androgen insensitivity. Rats with this syndrome are called testicular feminized (TFM).<ref>PMID:2341409</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ANDR_RAT ANDR_RAT] Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3 (By similarity).<ref>PMID:17181141</ref> <ref>PMID:17008401</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ih/2ihq_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ihq ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate. |
| | | | |
| - | '''Crystal Structure of the Rat Androgen Receptor Ligand Binding Domian Complex with an N-Aryl-Hydroxybicyclohydantoin'''
| + | Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold.,Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR Jr, An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG J Med Chem. 2006 Dec 28;49(26):7596-9. PMID:17181141<ref>PMID:17181141</ref> |
| - | | + | |
| - | | + | |
| - | ==Overview==
| + | |
| - | A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 2IHQ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IHQ OCA].
| + | </div> |
| | + | <div class="pdbe-citations 2ihq" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold., Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR Jr, An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG, J Med Chem. 2006 Dec 28;49(26):7596-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17181141 17181141]
| + | *[[Androgen receptor 3D structures|Androgen receptor 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Rattus norvegicus]] | | [[Category: Rattus norvegicus]] |
| - | [[Category: Single protein]]
| + | [[Category: Sack JS]] |
| - | [[Category: Sack, J S.]] | + | |
| - | [[Category: Androgen receptor]]
| + | |
| - | [[Category: Ligand-binding domain]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Steroid receptor]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:31:03 2008''
| + | |
| Structural highlights
Disease
ANDR_RAT Note=Defects in Ar are a cause of androgen insensitivity. Rats with this syndrome are called testicular feminized (TFM).[1]
Function
ANDR_RAT Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3 (By similarity).[2] [3]
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
A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold.,Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR Jr, An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG J Med Chem. 2006 Dec 28;49(26):7596-9. PMID:17181141[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yarbrough WG, Quarmby VE, Simental JA, Joseph DR, Sar M, Lubahn DB, Olsen KL, French FS, Wilson EM. A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat. J Biol Chem. 1990 May 25;265(15):8893-900. PMID:2341409
- ↑ Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR Jr, An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG. Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold. J Med Chem. 2006 Dec 28;49(26):7596-9. PMID:17181141 doi:10.1021/jm061101w
- ↑ 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. 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. Endocrinology. 2007 Jan;148(1):4-12. Epub 2006 Sep 28. PMID:17008401 doi:10.1210/en.2006-0843
- ↑ Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR Jr, An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG. Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold. J Med Chem. 2006 Dec 28;49(26):7596-9. PMID:17181141 doi:10.1021/jm061101w
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