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PMID: 9808622 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structure and specificity of nuclear receptor-coactivator interactions.

Genes & development ·Vol. 12 ·No. 21 ·1998-11-01 ·Pages 3343-56

Darimont BD, Wagner RL, Apriletti JW, Stallcup MR, Kushner PJ, Baxter JD, Fletterick RJ, Yamamoto KR

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.

MeSH Terms
Amino Acid Sequence Binding, Competitive Crystallography, X-Ray Gene Expression Regulation Models, Molecular Molecular Sequence Data Nuclear Receptor Coactivator 2 Peptide Fragments/chemistry,genetics,metabolism Protein Structure, Secondary Protein Structure, Tertiary Receptors, Cytoplasmic and Nuclear/chemistry,genetics,metabolism Receptors, Glucocorticoid/chemistry,genetics,metabolism Receptors, Thyroid Hormone/chemistry,genetics,metabolism Transcription Factors/metabolism,physiology Transcriptional Activation
Chemicals
Nuclear Receptor Coactivator 2 Peptide Fragments Receptors, Cytoplasmic and Nuclear Receptors, Glucocorticoid Receptors, Thyroid Hormone Transcription Factors
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Darimont B D
Department of Cellular and Molecular Pharmacology, University of California at San Francisco (UCSF), San Francisco, California 94143 USA.
Wagner R L
Apriletti J W
Stallcup M R
Kushner P J
Baxter J D
Fletterick R J
Yamamoto K R
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.12.21.3343
Published
1998-11-01
Pages
3343-56
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC317236
Subset
IM
Databases
PDB
1BSX
External Links
PubMed source DOI: 10.1101/gad.12.21.3343 PMC Full Text View journal details
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