Crystal structure of the human estrogen receptor alpha ligand-binding domain: Estradiol comple

This work represents the solution of the crystal structure of the complex formed by estradiol and the human estrogen receptor alpha ligand-binding domain (hERalphaLBD) to 2.8 A, and the comparison of this structure with the previously reported structures of the progesterone receptor-progesterone, thyroid receptor-thyroid hormone, and retinoic acid receptor-retinoic acid complexes, as well as with the apo-9-cis retinoic acid receptor LBD. A comparison of hormone binding between the estrogen and progesterone receptors reveals specificity determinants formed by a common structural theme of mutually supported van der Waals and hydrogen-bonded interactions involving highly conserved residues. The common architecture of the steroid receptors shows substantial dissimilarities to the thyroid hormone and retinoic acid receptors' ligand-protein interactions. Mapping of previous mutagenesis data, using both this structure and other previously solved complexes, points to a coactivator-binding surface that includes the region around the "signature sequence" as well as helix 12, where the ligand-dependent conformation of the activation function 2 (AF-2) core is similar in all previously solved steroid/nuclear receptor LBDs. An unexpected oxidative event, the fortuitous covalent crosslinking of exposed cysteines in the final loop of this structure, has produced a shift in helix 12 into a non-cognate formation, which necessitates the use of other structural data, including other hERalphaLBD structures, to complete these analyses.