2ax6
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Crystal Structure Of The Androgen Receptor Ligand Binding Domain T877A Mutant In Complex With Hydroxyflutamide
OverviewOverview
The mechanism by which the androgen receptor (AR) distinguishes between, agonist and antagonist ligands is poorly understood. AR antagonists are, currently used to treat prostate cancer. However, mutations commonly, develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which, structurally resemble the nonsteroidal AR antagonists bicalutamide and, hydroxyflutamide but act as agonists for the androgen receptor in a, tissue-selective manner. To investigate why subtle structural changes to, both the ligand and the receptor (i.e. mutations) result in drastic, changes in activity, we studied structure-activity relationships for, nonsteroidal AR ligands through crystallography and site-directed, mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1, and R-3. These studies provide the first crystallographic evidence of the, mechanism by which nonsteroidal ligands interact with the wild type AR. We, have shown that changes induced to the positions of Trp-741, Thr-877, and, Met-895 allow for ligand accommodation within the AR binding pocket and, that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and, the ketone of hydroxyflutamide is present when bound to the T877A AR, variant. Additionally, we demonstrated that R-bicalutamide stimulates, transcriptional activation in AR harboring the M895T point mutation. As a, whole, these studies provide critical new insight for receptor-based drug, design of nonsteroidal AR agonists and antagonists.
DiseaseDisease
Known diseases associated with this structure: Androgen insensitivity OMIM:[313700], Breast cancer, male, with Reifenstein syndrome OMIM:[313700], Hypospadias, perineal OMIM:[313700], Prostate cancer OMIM:[313700], Prostate cancer, susceptibility to OMIM:[313700], Spinal and bulbar muscular atrophy of Kennedy OMIM:[313700]
About this StructureAbout this Structure
2AX6 is a Single protein structure of sequence from Homo sapiens with HFT as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for accommodation of nonsteroidal ligands in the androgen receptor., Bohl CE, Miller DD, Chen J, Bell CE, Dalton JT, J Biol Chem. 2005 Nov 11;280(45):37747-54. Epub 2005 Aug 29. PMID:16129672
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