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| Our Crystal Structures | The Pharmacology X-ray lab |
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Analysis of Nuclear Receptor Complexes with DNA and Ligands
We use X-ray crystallography and other biophysical studies to
visualize transcription factors in their revealing complexes and
assemblies. The nuclear hormone receptors are the largest
known superfamily of eukaryotic transcription factors, with
nearly 200 distinct members. In some cases, the receptors
act as combinatorial transcription factors by forming pairwise
interactions on DNA control sites. The combinatorial
assemblies produce a cooperative enhancement in DNA
affinity and facilitate the binding of coactivators and
corepressors to the control sites. Hormone responsive genes
are regulated by the nuclear receptors in response to
lipophilic molecules like steroids, retinoids, thyroid hormone,
vitamin D3 and other molecules. Our work is directed at understanding: a) the stereochemical basis for DNA target recognition and b) the determinants of hormone binding to the receptor's ligand- binding domain. Our work on the DNA-complexes has resulted in high resolution crystal structures of the following r homodimers and heterodimers of the 9-cis retinoic acid receptor (RXR) with DNA: RXR-TR, RXR-RXR, RXR-RAR. In addition, we have solved the structure of the DNA-binding homodimeric complex of the orphan receptor RevErb. To also understand the basis for ligand specificity, we have over-expressed a number of receptor ligand-binding domains and are pursuing co-crystallization studies with these polypeptides bound to their cognate ligands. |
