Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

Irina N. Krylova, Elena P. Sablin, Jamie Moore, Robert X. Xu, Gregory M. Waitt, J. Andrew MacKay, Dalia Juzumiene, Jane M. Bynum, Kevin Madauss, Valerie Montana, Lioudmila Lebedeva, Miyuki Suzawa, Jon D. Williams, Shawn P. Williams, Rodney K. Guy, Joseph W. Thornton, Robert J. Fletterick, Timothy M. Willson, Holly A. Ingraham

Research output: Contribution to journalArticlepeer-review

351 Scopus citations


Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members - mouse and human SF-1 and human LRH-1 - which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.

Original languageEnglish
Pages (from-to)343-355
Number of pages13
Issue number3
StatePublished - Feb 11 2005

Bibliographical note

Funding Information:
We would like to thank Drs. D. Julius, K. Shokat, D. Stokoe, S. Wadekar, N. Jouravel, D. Moore, and F. Szoka for critical comments, experimental suggestions, and reagents. The IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology. We would like to thank Drs. Cheng Yang and Joseph Ferrara from Rigaku/MSC Inc. for an invitation to this facility. This work was funded by NIH 1R21-GM70792-1 and the Oregon Medical Research Foundation to J.W.T., a HHMI predoctoral fellowship to J.A.M., and a NIDDK-PO1 support to R.J.F., R.K.G., and H.A.I.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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