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.

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. Research Abstract Details 

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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. Abstract Text:

Casey E Bohl,Zengru Wu,Duane D Miller,Charles E Bell,James T Dalton,

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.

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. Publishing Authors By Initials

CE Bohl,Z Wu,DD Miller,CE Bell,JT Dalton,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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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. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 13648-55

Journal Abbreviation:

ISSN: 0021-9258

DAY: 20

MONTH: 02

YEAR: 2007

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. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

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. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: metabolism

Chemical & Substance for Abstract: 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. Information

Substance Name: Cyproterone Acetate

Registry Number: 427-51-0

Grant and Affiliation Information for 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.

AFFILIATION: Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: R01 DK59800

ACRONYM: DK

MEDLINETA: J Biol Chem

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