2oz7: Difference between revisions
New page: left|200px<br /> <applet load="2oz7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2oz7, resolution 1.80Å" /> '''Crystal structure o... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2oz7. | [[Image:2oz7.jpg|left|200px]]<br /><applet load="2oz7" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2oz7" size=" | |||
caption="2oz7, resolution 1.80Å" /> | caption="2oz7, resolution 1.80Å" /> | ||
'''Crystal structure of the human androgen receptor T877A mutant ligand-binding domain with cyproterone acetate'''<br /> | '''Crystal structure of the human androgen receptor T877A mutant ligand-binding domain with cyproterone acetate'''<br /> | ||
| Line 6: | Line 5: | ||
==Overview== | ==Overview== | ||
Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in, the treatment of prostate cancer. Compared with steroidal agonists for the, androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier, in structure and therefore seemingly incompatible with the binding pockets, observed in currently available x-ray crystal structures of the AR, ligand-binding domain (LBD). We solved the x-ray crystal structure of the, human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known, to increase the agonist activity of CPA and therefore facilitate, purification and crystal formation of the receptor.drug complex. The, structure demonstrates that bulk from the 17alpha-acetate group of CPA, induces movement of the Leu-701 side chain, which results in partial, unfolding of the C-terminal end of helix 11 and displacement of the loop, between helices 11 and 12 in comparison to all other AR LBD crystal, structures published to date. This structural alteration leads to an, expansion of the AR binding cavity to include an additional pocket, bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880., Further, we found that CPA invokes transcriptional activation in the L701A, AR at low nanomolar concentrations similar to the T877A mutant. Analogous, mutations in the glucocorticoid receptor (GR) and progesterone receptor, were constructed, and we found that CPA was also converted into a potent, agonist in the M560A GR. Altogether, these data offer information for, structure-based drug design, elucidate flexible regions of the AR LBD, and, provide insight as to how CPA antagonizes the AR and GR. | Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in, the treatment of prostate cancer. Compared with steroidal agonists for the, androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier, in structure and therefore seemingly incompatible with the binding pockets, observed in currently available x-ray crystal structures of the AR, ligand-binding domain (LBD). We solved the x-ray crystal structure of the, human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known, to increase the agonist activity of CPA and therefore facilitate, purification and crystal formation of the receptor.drug complex. The, structure demonstrates that bulk from the 17alpha-acetate group of CPA, induces movement of the Leu-701 side chain, which results in partial, unfolding of the C-terminal end of helix 11 and displacement of the loop, between helices 11 and 12 in comparison to all other AR LBD crystal, structures published to date. This structural alteration leads to an, expansion of the AR binding cavity to include an additional pocket, bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880., Further, we found that CPA invokes transcriptional activation in the L701A, AR at low nanomolar concentrations similar to the T877A mutant. Analogous, mutations in the glucocorticoid receptor (GR) and progesterone receptor, were constructed, and we found that CPA was also converted into a potent, agonist in the M560A GR. Altogether, these data offer information for, structure-based drug design, elucidate flexible regions of the AR LBD, and, provide insight as to how CPA antagonizes the AR and GR. | ||
==About this Structure== | ==About this Structure== | ||
2OZ7 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 CA4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2OZ7 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=CA4:'>CA4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OZ7 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 27: | Line 23: | ||
[[Category: prostate cancer]] | [[Category: prostate cancer]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:57:07 2008'' | ||
Revision as of 14:57, 23 January 2008
|
Crystal structure of the human androgen receptor T877A mutant ligand-binding domain with cyproterone acetate
OverviewOverview
Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in, the treatment of prostate cancer. Compared with steroidal agonists for the, androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier, in structure and therefore seemingly incompatible with the binding pockets, observed in currently available x-ray crystal structures of the AR, ligand-binding domain (LBD). We solved the x-ray crystal structure of the, human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known, to increase the agonist activity of CPA and therefore facilitate, purification and crystal formation of the receptor.drug complex. The, structure demonstrates that bulk from the 17alpha-acetate group of CPA, induces movement of the Leu-701 side chain, which results in partial, unfolding of the C-terminal end of helix 11 and displacement of the loop, between helices 11 and 12 in comparison to all other AR LBD crystal, structures published to date. This structural alteration leads to an, expansion of the AR binding cavity to include an additional pocket, bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880., Further, we found that CPA invokes transcriptional activation in the L701A, AR at low nanomolar concentrations similar to the T877A mutant. Analogous, mutations in the glucocorticoid receptor (GR) and progesterone receptor, were constructed, and we found that CPA was also converted into a potent, agonist in the M560A GR. Altogether, these data offer information for, structure-based drug design, elucidate flexible regions of the AR LBD, and, provide insight as to how CPA antagonizes the AR and GR.
About this StructureAbout this Structure
2OZ7 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design., Bohl CE, Wu Z, Miller DD, Bell CE, Dalton JT, J Biol Chem. 2007 May 4;282(18):13648-55. Epub 2007 Feb 20. PMID:17311914
Page seeded by OCA on Wed Jan 23 13:57:07 2008