2oz7: Difference between revisions
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|PDB= 2oz7 |SIZE=350|CAPTION= <scene name='initialview01'>2oz7</scene>, resolution 1.80Å | |PDB= 2oz7 |SIZE=350|CAPTION= <scene name='initialview01'>2oz7</scene>, resolution 1.80Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=CA4:CYPROTERONE ACETATE'>CA4</scene> | |LIGAND= <scene name='pdbligand=CA4:CYPROTERONE+ACETATE'>CA4</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= AR, DHTR, NR3C4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= AR, DHTR, NR3C4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY=[[2axa|2AXA]], [[1z95|1Z95]], [[2ax6|2AX6]], [[2ax7|2AX7]], [[i138|I138]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2oz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oz7 OCA], [http://www.ebi.ac.uk/pdbsum/2oz7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2oz7 RCSB]</span> | |||
}} | }} | ||
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==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== | ||
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[[Category: Miller, D D.]] | [[Category: Miller, D D.]] | ||
[[Category: Wu, Z.]] | [[Category: Wu, Z.]] | ||
[[Category: androgen receptor]] | [[Category: androgen receptor]] | ||
[[Category: anti-androgen]] | [[Category: anti-androgen]] | ||
[[Category: prostate cancer]] | [[Category: prostate cancer]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:25:24 2008'' | ||