2A66

Human Liver Receptor Homologue DNA-Binding Domain (hLRH-1 DBD) in Complex with dsDNA from the hCYP7A1 Promoter

Summary for 2A66

• Entry DOI: 10.2210/pdb2a66/pdb
• Descriptor: 5'-D(*GP*TP*TP*CP*AP*AP*GP*GP*CP*CP*AP*G)-3', 5'-D(*CP*TP*GP*GP*CP*CP*TP*TP*GP*AP*AP*C)-3', Orphan nuclear receptor NR5A2, ... (6 entities in total)
• Functional Keywords: nuclear receptor, protein-dna complex, zinc finger, dna-binding domain, transcription factor, ftz-f1, c-terminal extension, transcription-dna complex, transcription/dna
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : O00482
• Total number of polymer chains: 3
• Total formula weight: 20725.05

Authors

Solomon, I.H.,Hager, J.M.,Safi, R.,McDonnell, D.P.,Redinbo, M.R.,Ortlund, E.A. (deposition date: 2005-07-01, release date: 2005-12-06, Last modification date: 2023-08-23)

Primary citation

Solomon, I.H.,Hager, J.M.,Safi, R.,McDonnell, D.P.,Redinbo, M.R.,Ortlund, E.A.
Crystal Structure of the Human LRH-1 DBD-DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity.
J.Mol.Biol., 354:1091-1102, 2005

PubMed 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.

PubMed: 16289203
DOI: 10.1016/j.jmb.2005.10.009

Experimental method

X-RAY DIFFRACTION (2.2 Å)