1u3s: Difference between revisions

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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="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1u3s, resolution 2.50Å" />

'''Crystal Structure of Estrogen Receptor beta complexed with WAY-797'''<br />

==Overview==

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.

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==

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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1U3S OCA].

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==

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[[Category: Homo sapiens]]

[[Category: Single protein]]

[[Category: Collini, M.D.]]

[[Category: Collini, M D.]]

[[Category: Dinh, T.]]

[[Category: Gunawan, I.]]

[[Category: Harris, H.A.]]

[[Category: Harris, H A.]]

[[Category: Henderson, R.A.]]

[[Category: Henderson, R A.]]

[[Category: Jr., J.C.Keith.]]

[[Category: Jr., J C.Keith.]]

[[Category: Malamas, M.S.]]

[[Category: Malamas, M S.]]

[[Category: Manas, E.S.]]

[[Category: Manas, E S.]]

[[Category: McDevitt, R.E.]]

[[Category: McDevitt, R E.]]

[[Category: Miller, C.P.]]

[[Category: Miller, C P.]]

[[Category: Xu, Z.B.]]

[[Category: Xu, Z B.]]

[[Category: 797]]

[[Category: agonist]]

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[[Category: transcription factor]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 19~~:31:~~14 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:21 2008''

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@@ Line 1: / Line 1: @@
-[[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="450" color="white" frame="true" align="right" spinBox="true"
 caption="1u3s, resolution 2.50&Aring;" />
 '''Crystal Structure of Estrogen Receptor beta complexed with WAY-797'''<br />
 ==Overview==
-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 &gt;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) --&gt; 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, &gt;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.
+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 &gt;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) --&gt; 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 &gt;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==
-U3S 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1U3S OCA].
+U3S 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==
@@ Line 14: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Collini, M.D.]]
+[[Category: Collini, M D.]]
 [[Category: Dinh, T.]]
 [[Category: Gunawan, I.]]
-[[Category: Harris, H.A.]]
+[[Category: Harris, H A.]]
-[[Category: Henderson, R.A.]]
+[[Category: Henderson, R A.]]
-[[Category: Jr., J.C.Keith.]]
+[[Category: Jr., J C.Keith.]]
-[[Category: Malamas, M.S.]]
+[[Category: Malamas, M S.]]
-[[Category: Manas, E.S.]]
+[[Category: Manas, E S.]]
-[[Category: McDevitt, R.E.]]
+[[Category: McDevitt, R E.]]
-[[Category: Miller, C.P.]]
+[[Category: Miller, C P.]]
-[[Category: Xu, Z.B.]]
+[[Category: Xu, Z B.]]
 [[Category: 797]]
 [[Category: agonist]]
@@ Line 35: / Line 34: @@
 [[Category: transcription factor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:31:14 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:21 2008''