Structural and Functional Analysis of Androgen Receptor-DNA Interactions

摘要

Our objective was to use X-ray crystallography to determine the basis for specific interactions between the Androgen receptor and its DNA targets, in order to understand how the receptor can recognize two different bipartite DNA response elements with diametrically opposing arrangements. Our research has identified a variant of the AR DNA binding domain that yields large, single lattice crystals when bound to a direct repeat response element. The 3-dimensional crystal structure of the androgen receptor (AR) DNA binding domain (DBD) bound to a selective ADR3, determined at 3.1 A resolution, reveals an unexpected head-to-head arrangement of the two protomers, rather than the expected head- to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared to the glucocorticoid receptor (GR), the DBD dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for non- consensus response elements. This increased interfacial stability compared to the other steroid receptors may account for the selective binding of AR to ADR3 response elements.