2AB2

Mineralocorticoid Receptor Double Mutant with Bound Spironolactone

Summary for 2AB2

• Entry DOI: 10.2210/pdb2ab2/pdb
• Related: 2AA2 2AA5 2AA6 2AA7 2AAX
• Descriptor: Mineralocorticoid receptor, SPIRONOLACTONE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mineralocorticoid receptor, mr, nuclear receptor, steroid receptor, spironolactone, hypertension, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P08235
• Total number of polymer chains: 2
• Total formula weight: 64202.41

Authors

Bledsoe, R.K.,Madauss, K.P.,Holt, J.A.,Apolito, C.J.,Lambert, M.H.,Pearce, K.H.,Stanley, T.B.,Stewart, E.L.,Trump, R.P.,Willson, T.M.,Williams, S.P. (deposition date: 2005-07-14, release date: 2005-07-26, Last modification date: 2024-02-14)

Primary citation

Bledsoe, R.K.,Madauss, K.P.,Holt, J.A.,Apolito, C.J.,Lambert, M.H.,Pearce, K.H.,Stanley, T.B.,Stewart, E.L.,Trump, R.P.,Willson, T.M.,Williams, S.P.
A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor
J.Biol.Chem., 280:31283-31293, 2005

PubMed Abstract: 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.

PubMed: 15967794
DOI: 10.1074/jbc.M504098200

Experimental method

X-RAY DIFFRACTION (1.85 Å)