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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Miller, Duane D. Bell, Charles E. Dalton, James T. Bohl, Casey E. Wu, Zengru |
| Description | Author Affiliation: Bohl CE ( Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.) |
| Abstract | 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 18 |
| Volume Number | 282 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2007-05-04 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cyproterone Acetate Chemistry Receptors, Androgen Amino Acid Substitution Amino Acids Crystallography, X-Ray Metabolism Drug Design Ligands Mutation, Missense Protein Binding Genetics Protein Structure, Secondary Protein Structure, Tertiary Receptors, Glucocorticoid Receptors, Progesterone Structural Homology, Protein Structure-Activity Relationship Comparative Study Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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