1u3s: Difference between revisions
New page: left|200px<br /> <applet load="1u3s" size="450" color="white" frame="true" align="right" spinBox="true" caption="1u3s, resolution 2.50Å" /> '''Crystal Structure o... |
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[[Image:1u3s.gif|left|200px]]<br /> | [[Image:1u3s.gif|left|200px]]<br /><applet load="1u3s" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1u3s" size=" | |||
caption="1u3s, resolution 2.50Å" /> | caption="1u3s, resolution 2.50Å" /> | ||
'''Crystal Structure of Estrogen Receptor beta complexed with WAY-797'''<br /> | '''Crystal Structure of Estrogen Receptor beta complexed with WAY-797'''<br /> | ||
==Overview== | ==Overview== | ||
New diphenolic azoles as highly selective estrogen receptor-beta agonists | New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions. | ||
==About this Structure== | ==About this Structure== | ||
1U3S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 797 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1U3S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=797:'>797</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U3S OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Collini, M | [[Category: Collini, M D.]] | ||
[[Category: Dinh, T.]] | [[Category: Dinh, T.]] | ||
[[Category: Gunawan, I.]] | [[Category: Gunawan, I.]] | ||
[[Category: Harris, H | [[Category: Harris, H A.]] | ||
[[Category: Henderson, R | [[Category: Henderson, R A.]] | ||
[[Category: Jr., J | [[Category: Jr., J C.Keith.]] | ||
[[Category: Malamas, M | [[Category: Malamas, M S.]] | ||
[[Category: Manas, E | [[Category: Manas, E S.]] | ||
[[Category: McDevitt, R | [[Category: McDevitt, R E.]] | ||
[[Category: Miller, C | [[Category: Miller, C P.]] | ||
[[Category: Xu, Z | [[Category: Xu, Z B.]] | ||
[[Category: 797]] | [[Category: 797]] | ||
[[Category: agonist]] | [[Category: agonist]] | ||
| Line 35: | Line 34: | ||
[[Category: transcription factor]] | [[Category: transcription factor]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:21 2008'' | ||
Revision as of 16:20, 21 February 2008
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Crystal Structure of Estrogen Receptor beta complexed with WAY-797
OverviewOverview
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
About this StructureAbout this Structure
1U3S is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands., Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC Jr, Harris HA, J Med Chem. 2004 Oct 7;47(21):5021-40. PMID:15456246
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