LIGAND-INDUCED CONFORMATIONAL DYNAMICS IN ANDROGEN RECEPTOR & CO-ACTIVATORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ligand-induced conformational perturbations in androgen receptor (AR) are important in coactivator recruitment and transactivation. However, molecular rearrangements in AR ligand binding domain (AR-LBD) associated with agonist binding and their kinetic and thermodynamic parameters are poorly understood. The study is testing the hypothesis that receptor conformation is flexible in the absence of ligand but achieves a distinct, energetically stable form upon ligand binding. LFD core facilities are central to our specific aims. We are utilizing steady state second derivative absorption and emission spectroscopy, pressure and temperature perturbations, and bis-ANS partitioning to investigate changes in microenvironment of intrinsic tyrosine and tryptophan residues and determine the kinetics and thermodynamics of the conformational changes in AR-LBD after DHT binding.FCS and confocal imaging capabilities available through collaboration with Dr. Theodore Hazlett are allowing us to examine, for the first time, the stoichiometry of ligand:receptor interactions and dynamics of rearrangement in the protein structure upon ligand binding.