Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance.

Laboratories for Reproductive Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Molecular Cell (Impact Factor: 15.28). 12/2004; 16(3):425-38. DOI: 10.1016/j.molcel.2004.09.036
Source: PubMed

ABSTRACT The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH(2)-terminal transactivation domain in the steroid receptor subfamily.

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    Androgen Receptors: Structural Biology, Genetics and Molecular Defects., 2014 edited by Silvia Socorro, 01/2014: chapter Structural and Functional Analysis of the Androgen Receptor in Disease: pages 53-81; Nova., ISBN: 978-1-62948-693-2
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    ABSTRACT: The Androgen Receptor (AR) is a transcription factor that has a pivotal role in the occurrence and progression of prostate cancer (PCa). The AR is activated by androgens that bind to its ligand-binding domain (LBD), causing the transcription factor to enter the nucleus and interact with genes via its conserved DNA-binding domain (DBD). Treatment for PCa involves reducing androgen production or using anti-androgen drugs to block the interaction of hormones with the AR-LBD. Eventually the disease changes into a castration resistant form (CRPC) where LBD mutations render anti-androgens ineffective or where constitutively active AR splice variants, lacking the LBD, become over-expressed. Recently, we identified a surfaced exposed pocket on the AR-DBD as an alternative drug-target site for AR inhibition. Here, we demonstrate that small molecules designed to selectively bind the pocket effectively block transcriptional activity of full-length and splice variant AR forms at low- to sub- μM concentrations. The inhibition is lost when residues involved in drug interactions are mutated. Furthermore, the compounds did not impede nuclear localization of the AR and blocked interactions with chromatin, indicating the interference of DNA binding with the nuclear form of the transcription factor. Finally, we demonstrate the inhibition of gene expression and tumor volume in mouse xenografts. Our results indicate that the AR-DBD has a surface site that can be targeted to inhibit all forms of the AR, including Enzalutamide resistant and constitutively active splice variants and thus may serve as a potential avenue for the treatment of recurrent and metastatic prostate cancer.
    Journal of Biological Chemistry 08/2014; · 4.65 Impact Factor
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    ABSTRACT: Since its introduction in 2003, the Shape Signatures method has been successfully applied in a number of drug design projects. Because it uses a ray-tracing approach to directly measure molecular shape and properties (as opposed to relying on chemical structure), it excels at scaffold hopping, and is extraordinarily easy to use. Despite its advantages, a significant drawback of the method has hampered its application to certain classes of problems; namely, when the chemical structures considered are large and contain heterogeneous ring-systems, the method produces descriptors that tend to merely measure the overall size of the molecule, and begin to lose selective power. To remedy this, the approach has been reformulated to automatically decompose compounds into fragments using ring systems as anchors, and to likewise partition the ray-trace in accordance with the fragment assignments. Subsequently, descriptors are generated that are fragment-based, and query and target molecules are compared by mapping query fragments onto target fragments in all ways consistent with the underlying chemical connectivity. This has proven to greatly extend the selective power of the method, while maintaining the ease of use and scaffold-hopping capabilities that characterized the original implementation. In this work, we provide a full conceptual description of the next generation Shape Signatures, and we underline the advantages of the method by discussing its practical applications to ligand-based virtual screening. The new approach can also be applied in receptor-based mode, where protein-binding sites (partitioned into subsites) can be matched against the new fragment-based Shape Signatures descriptors of library compounds.
    Journal of Computer-Aided Molecular Design 12/2013; · 3.17 Impact Factor

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