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Structure and specificity of nuclear receptor-coactivator interactions
B D Darimont1, R L Wagner, J W Apriletti
1Department of Cellular and Molecular Pharmacology, University of California at San Francisco (UCSF), San Francisco, California 94143 USA.
Genes & Development
|November 10, 1998
Summary
Thyroid hormone receptor (THR) and coactivator GRIP1 interaction involves a hydrophobic groove and LxxLL motif. Specific side chains at the interface provide binding specificity, enabling flexible yet precise gene regulation.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Combinatorial regulation of transcription allows for precise gene expression control through multiprotein complexes.
- Understanding these interactions is crucial for deciphering cellular signaling pathways.
Purpose of the Study:
- To elucidate the structural basis of the interaction between the thyroid hormone receptor (THR) ligand binding domain (LBD) and the coactivator GRIP1.
- To identify key structural elements responsible for the specificity and flexibility of this transcriptional regulatory complex.
Main Methods:
- Biochemical analyses to study protein-protein interactions.
- Crystallographic analysis to determine the three-dimensional structure of the receptor-coactivator complex.
Main Results:
- Hormone binding to the THR-LBD induces a hydrophobic groove.
- This groove interacts with an alpha-helix containing an LxxLL motif from the coactivator GRIP1.
- Adjacent residues to the LxxLL motif modulate binding affinity and receptor specificity.
Conclusions:
- The interaction between amphipathic alpha-helices and hydrophobic grooves is a common feature in regulatory complexes.
- These shared structural elements provide flexibility in combinatorial gene regulation.
- Specificity is conferred by the distinct side chains at the protein-protein interface.