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Mol. Cell. Biol. doi:10.1128/MCB.01541-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, Michigan 49503; Steroid Hormones Section, NIDDK/CEB, National Institutes of Health, Bethesda, MD 20892-1772

^* To whom correspondence should be addressed. Email: eric.xu{at}vai.org.

	Abstract

A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator-1 reveals that the GR ligand binding pocket is expanded to a size of 1070 ų, effectively doubling the size of the GR DEX-binding pocket of 540 ų, and yet leaving the structure of the coactivator binding site intact. DAC only occupies 50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that can not be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and non-steroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.