Abstract
Mineralocorticoid receptor (MR) controls sodium homeostasis and blood pressure through hormone binding and coactivator recruitment. Here, we report a 1.95 A crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4). Through a combination of biochemical and structural analyses, we demonstrate that SRC1-4 is the most potent MR binding motif and mutations that disrupt the MR/SRC1-4 interactions abolish the ability of the full-length SRC1 to coactivate MR. The structure also reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Mutations swapping a single residue at position 848 from helix H7 between MR and glucocorticoid receptor (GR) switch their hormone specificity. Together, these findings provide critical insights into the molecular basis of hormone binding and coactivator recognition by MR and related steroid receptors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aldosterone / metabolism
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Amino Acid Motifs / genetics
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Amino Acid Sequence
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Animals
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Binding, Competitive
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COS Cells
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Chlorocebus aethiops
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Corticosterone / metabolism
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Crystallography, X-Ray
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Genes, Reporter / genetics
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Histone Acetyltransferases
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Hormones / metabolism*
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Humans
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Mutation
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Nuclear Receptor Coactivator 1
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Receptors, Mineralocorticoid / chemistry*
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Receptors, Mineralocorticoid / genetics
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Receptors, Mineralocorticoid / metabolism
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Receptors, Steroid / chemistry
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Trans-Activators / genetics
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Transcription Factors / chemistry*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / genetics
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Transfection
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Two-Hybrid System Techniques
Substances
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Hormones
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Peptide Fragments
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Receptors, Mineralocorticoid
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Receptors, Steroid
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Recombinant Proteins
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Trans-Activators
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Transcription Factors
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Aldosterone
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Histone Acetyltransferases
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NCOA1 protein, human
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Nuclear Receptor Coactivator 1
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Corticosterone