MOLECULAR RECOGNITION IN STEROID SIGNALING

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This study seeks to use X-ray crystallography to understand the rich interfacial chemistry involved in steroid binding and discrimination by the nuclear steroid receptors. The steroid binding induces receptor conformational changes that ultimately modulate transcription from steroid responsive genes. To understand the stereochemical mechanisms of steroid recognition in this family, it is essential to visualize the binding determinants located within the receptors' ligand binding domains (LBD). A cross examination of several sterol binding interactions will reveal both the conserved mechanisms of recognition and the unique specifying features that mediate ligand discrimination. Because point mutations in a number of LBDs have been associated with steroid insensitivity, profound developmental dysfunction and cancer, the structures we seek may be used to pinpoint the precise defects. The androgen receptor, overproduced and bound to a synthetic testosterone analog presents the fist candidate for our structural studies. This receptor specifically binds both steroid and non-steroid androgen antagonists used for the treatment of prostate cancer. Numerous point mutations associated with androgen insensitivity syndrome and have been mapped to its LBD. In addition, there are an increasing number of endocrine disrupters which appear to target this receptor. We propose to expand our preliminary diffraction studies in order to: 1) learn the mechanisms of agonist versus antagonist recognition and the corresponding conformational changes induced in a single receptor, and 2) understand the mechanisms of steroid discrimination through analysis of multiple different LBD-ligand interactions.