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Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.

Publication ,  Journal Article
Solomon, IH; Hager, JM; Safi, R; McDonnell, DP; Redinbo, MR; Ortlund, EA
Published in: J Mol Biol
December 16, 2005

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.

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Published In

J Mol Biol

DOI

ISSN

0022-2836

Publication Date

December 16, 2005

Volume

354

Issue

5

Start / End Page

1091 / 1102

Location

Netherlands

Related Subject Headings

  • Water
  • Transcription, Genetic
  • Transcription Factors
  • Response Elements
  • Receptors, Cytoplasmic and Nuclear
  • Protein Structure, Tertiary
  • Protein Conformation
  • Protein Binding
  • Promoter Regions, Genetic
  • Oxygen
 

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Solomon, I. H., Hager, J. M., Safi, R., McDonnell, D. P., Redinbo, M. R., & Ortlund, E. A. (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(5), 1091–1102. https://doi.org/10.1016/j.jmb.2005.10.009
Solomon, Isaac H., Janet M. Hager, Rachid Safi, Donald P. McDonnell, Matthew R. Redinbo, and Eric A. Ortlund. “Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.J Mol Biol 354, no. 5 (December 16, 2005): 1091–1102. https://doi.org/10.1016/j.jmb.2005.10.009.
Solomon IH, Hager JM, Safi R, McDonnell DP, Redinbo MR, Ortlund EA. Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J Mol Biol. 2005 Dec 16;354(5):1091–102.
Solomon, Isaac H., et al. “Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.J Mol Biol, vol. 354, no. 5, Dec. 2005, pp. 1091–102. Pubmed, doi:10.1016/j.jmb.2005.10.009.
Solomon IH, Hager JM, Safi R, McDonnell DP, Redinbo MR, Ortlund EA. Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J Mol Biol. 2005 Dec 16;354(5):1091–1102.
Journal cover image

Published In

J Mol Biol

DOI

ISSN

0022-2836

Publication Date

December 16, 2005

Volume

354

Issue

5

Start / End Page

1091 / 1102

Location

Netherlands

Related Subject Headings

  • Water
  • Transcription, Genetic
  • Transcription Factors
  • Response Elements
  • Receptors, Cytoplasmic and Nuclear
  • Protein Structure, Tertiary
  • Protein Conformation
  • Protein Binding
  • Promoter Regions, Genetic
  • Oxygen