2q7j: Difference between revisions
New page: left|200px<br /> <applet load="2q7j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2q7j, resolution 1.90Å" /> '''The Wild Type Andro... |
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[[Image:2q7j.gif|left|200px]]<br /> | [[Image:2q7j.gif|left|200px]]<br /><applet load="2q7j" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2q7j, resolution 1.90Å" /> | caption="2q7j, resolution 1.90Å" /> | ||
'''The Wild Type Androgen Receptor Ligand Binding Domain Bound with Testosterone and a TIF2 box 3 Coactivator Peptide 740-753'''<br /> | '''The Wild Type Androgen Receptor Ligand Binding Domain Bound with Testosterone and a TIF2 box 3 Coactivator Peptide 740-753'''<br /> | ||
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==Overview== | ==Overview== | ||
The androgen receptor (AR) is transcriptionally activated by high affinity, binding of testosterone (T) or its 5a-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male, reproductive tract development. The molecular basis for the weaker, activity of T was investigated by determining T-bound ligand binding, domain crystal structures of wild-type AR and a prostate cancer somatic, mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly, identical interactions of T and DHT in the AR ligand binding pocket, correlate with similar rates of dissociation from an AR fragment, containing the ligand binding domain. However, T induces weaker AR FXXLF, and coactivator LXXLL motif interactions at activation function 2 (AF2)., Less effective FXXLF motif binding to AF2 accounts for faster T, dissociation from full-length AR. T can nevertheless acquire DHT-like, activity through an AR helix-10 H874Y prostate cancer mutation. The, Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from, exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to, rescue T induced AR activity by improving AF2 binding of FXXLF and LXXLL, motifs. Greater AR AF2 activity by improved core helix interactions is, supported by the effects of melanoma antigen gene protein-11, an AR, coregulator that binds the AR FXXLF motif and targets AF2 for activation., We conclude that T is a weaker androgen than DHT because of less favorable, T dependent AR FXXLF and coactivator LXXLL motif interactions at AF2. | The androgen receptor (AR) is transcriptionally activated by high affinity, binding of testosterone (T) or its 5a-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male, reproductive tract development. The molecular basis for the weaker, activity of T was investigated by determining T-bound ligand binding, domain crystal structures of wild-type AR and a prostate cancer somatic, mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly, identical interactions of T and DHT in the AR ligand binding pocket, correlate with similar rates of dissociation from an AR fragment, containing the ligand binding domain. However, T induces weaker AR FXXLF, and coactivator LXXLL motif interactions at activation function 2 (AF2)., Less effective FXXLF motif binding to AF2 accounts for faster T, dissociation from full-length AR. T can nevertheless acquire DHT-like, activity through an AR helix-10 H874Y prostate cancer mutation. The, Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from, exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to, rescue T induced AR activity by improving AF2 binding of FXXLF and LXXLL, motifs. Greater AR AF2 activity by improved core helix interactions is, supported by the effects of melanoma antigen gene protein-11, an AR, coregulator that binds the AR FXXLF motif and targets AF2 for activation., We conclude that T is a weaker androgen than DHT because of less favorable, T dependent AR FXXLF and coactivator LXXLL motif interactions at AF2. | ||
==About this Structure== | ==About this Structure== | ||
2Q7J is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, TES and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2Q7J is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=TES:'>TES</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q7J OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: tif2 boxiii coactivator peptide]] | [[Category: tif2 boxiii coactivator peptide]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:34:26 2008'' | ||
Revision as of 13:34, 23 January 2008
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The Wild Type Androgen Receptor Ligand Binding Domain Bound with Testosterone and a TIF2 box 3 Coactivator Peptide 740-753
OverviewOverview
The androgen receptor (AR) is transcriptionally activated by high affinity, binding of testosterone (T) or its 5a-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male, reproductive tract development. The molecular basis for the weaker, activity of T was investigated by determining T-bound ligand binding, domain crystal structures of wild-type AR and a prostate cancer somatic, mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly, identical interactions of T and DHT in the AR ligand binding pocket, correlate with similar rates of dissociation from an AR fragment, containing the ligand binding domain. However, T induces weaker AR FXXLF, and coactivator LXXLL motif interactions at activation function 2 (AF2)., Less effective FXXLF motif binding to AF2 accounts for faster T, dissociation from full-length AR. T can nevertheless acquire DHT-like, activity through an AR helix-10 H874Y prostate cancer mutation. The, Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from, exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to, rescue T induced AR activity by improving AF2 binding of FXXLF and LXXLL, motifs. Greater AR AF2 activity by improved core helix interactions is, supported by the effects of melanoma antigen gene protein-11, an AR, coregulator that binds the AR FXXLF motif and targets AF2 for activation., We conclude that T is a weaker androgen than DHT because of less favorable, T dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.
About this StructureAbout this Structure
2Q7J is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone., Askew EB, Gampe RT Jr, Stanley TB, Faggart JL, Wilson EM, J Biol Chem. 2007 Jun 25;. PMID:17591767
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