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PMID:16289203

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Citation

Solomon, IH, Hager, JM, Safi, R, McDonnell, DP, Redinbo, MR and Ortlund, EA (2005) Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J. Mol. Biol. 354:1091-102

Abstract

The DNA-binding and ligand-binding functions of nuclear receptors are localized to independent domains separated by a flexible hinge. The DNA-binding domain (DBD) of the human liver receptor homologue-1 (hLRH-1), which controls genes central to development and metabolic homeostasis, interacts with monomeric DNA response elements and contains an Ftz-F1 motif that is unique to the NR5A nuclear receptor subfamily. Here, we present the 2.2A resolution crystal structure of the hLRH-1 DBD in complex with duplex DNA, and elucidate the sequence-specific DNA contacts essential for the ability of LRH-1 to bind to DNA as a monomer. We show that the unique Ftz-F1 domain folds into a novel helix that packs against the DBD but does not contact DNA. Mutations expected to disrupt the positioning of the Ftz-F1 helix do not eliminate DNA binding but reduce the transcriptional activity of full-length LRH-1 significantly. Moreover, we find that altering the Ftz-F1 helix positioning eliminates the enhancement of LRH-1-mediated transcription by the coactivator GRIP1, an action that is associated primarily with the distantly located ligand-binding domain (LBD). Taken together, these results indicate that subtle structural changes in a nuclear receptor DBD can exert long-range functional effects on the LBD of a receptor, and significantly impact transcriptional regulation.

Links

PubMed Online version:10.1016/j.jmb.2005.10.009

Keywords

Alanine/metabolism; Amino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Arginine/chemistry; Base Sequence; Binding Sites; Carrier Proteins/metabolism; Crystallography, X-Ray; DNA/chemistry; DNA/metabolism; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/isolation & purification; DNA-Binding Proteins/metabolism; Fluorescence Polarization; Fushi Tarazu Transcription Factors/chemistry; Fushi Tarazu Transcription Factors/genetics; Fushi Tarazu Transcription Factors/metabolism; Genes, Reporter; Glutamic Acid/metabolism; Glycine/chemistry; Glycine/metabolism; HeLa Cells; Humans; Hydrogen Bonding; Ligands; Luciferases/metabolism; Models, Chemical; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins/metabolism; Oxygen/chemistry; Promoter Regions, Genetic; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear/chemistry; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/isolation & purification; Receptors, Cytoplasmic and Nuclear/metabolism; Response Elements; Transcription Factors/chemistry; Transcription Factors/genetics; Transcription Factors/isolation & purification; Transcription Factors/metabolism; Transcription, Genetic; Water/chemistry

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NR5A2

enables

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NR5A2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NR5A2

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR5A2

involved_in

GO:0009792: embryo development ending in birth or egg hatching

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR5A2

involved_in

GO:0042592: homeostatic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR5A2

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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