Abstract
Combinatorial regulation of transcription implies flexible yet precise assembly of multiprotein regulatory complexes in response to signals. Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator. Residues immediately adjacent to the motif modulate the affinity of the interaction; the motif and the adjacent sequences are employed to different extents in binding to different receptors. Such interactions of amphipathic alpha-helices with hydrophobic grooves define protein interfaces in other regulatory complexes as well. We suggest that these common structural elements impart flexibility to combinatorial regulation, whereas side chains at the interface impart specificity.
Publication types
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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.
MeSH terms
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Amino Acid Sequence
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Binding, Competitive
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Crystallography, X-Ray
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Gene Expression Regulation
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Models, Molecular
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Molecular Sequence Data
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Nuclear Receptor Coactivator 2
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptors, Cytoplasmic and Nuclear / chemistry*
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Glucocorticoid / chemistry
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism
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Receptors, Thyroid Hormone / chemistry
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / metabolism
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Transcription Factors / metabolism
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Transcription Factors / physiology
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Transcriptional Activation
Substances
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Nuclear Receptor Coactivator 2
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Peptide Fragments
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Receptors, Cytoplasmic and Nuclear
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Receptors, Glucocorticoid
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Receptors, Thyroid Hormone
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Transcription Factors