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J. Biol. Chem., Vol. 280, Issue 35, 31283-31293, September 2, 2005

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A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor^*

Randy K. Bledsoe, Kevin P. Madauss¶, Jason A. Holt||, Christopher J. Apolito, Millard H. Lambert¶, Kenneth H. Pearce, Thomas B. Stanley, Eugene L. Stewart¶, Ryan P. Trump**, Timothy M. Willson**, and Shawn P. Williams¶

From the Departments of Gene Expression and Protein Biochemistry, ^¶Computational, Analytical, and Structural Sciences, ^||High Throughput Biology, and ^**High Throughput Chemistry, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn⁷⁷⁰ which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr⁹⁴⁵ on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.

Received for publication, April 14, 2005 , and in revised form, June 8, 2005.

The atomic coordinates and structure factors (codes 2AA2, 2AA7, 2AA5, 2AA6, 2AAX, and 2AB2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Fig. 1.

To whom correspondence should be addressed: Dept. of Gene Expression and Protein Biochemistry, GlaxoSmithKline, Five Moore Dr., Research Triangle Park, NC 27709. Tel.: 919-483-3821; Fax: 919-483-0368; E-mail; randy.k.bledsoe{at}gsk.com.

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