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J Struct Biol. 2015 Dec;192(3):342-348. doi: 10.1016/j.jsb.2015.09.012. Epub 2015 Sep 28.

Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, United States.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, United States.
3
Joint Center for Structural Genomics, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, United States; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, United States.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, United States. Electronic address: Robert.Fletterick@ucsf.edu.

Abstract

The nuclear receptor LRH-1 (Liver Receptor Homolog-1, NR5A2) is a transcription factor that regulates gene expression programs critical for many aspects of metabolism and reproduction. Although LRH-1 is able to bind phospholipids, it is still considered an orphan nuclear receptor (NR) with an unknown regulatory hormone. Our prior cellular and structural studies demonstrated that the signaling phosphatidylinositols PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind and regulate SF-1 (Steroidogenic Factor-1, NR5A1), a close homolog of LRH-1. Here, we describe the crystal structure of human LRH-1 ligand binding domain (LBD) bound by PIP3 - the first phospholipid with a head group endogenous to mammals. We show that the phospholipid hormone binds LRH-1 with high affinity, stabilizing the receptor LBD. While the hydrophobic PIP3 tails (C16/C16) are buried inside the LRH-1 ligand binding pocket, the negatively charged PIP3 head group is presented on the receptor surface, similar to the phosphatidylinositol binding mode observed in the PIP3-SF-1 structure. Thus, data presented in this work reinforce our earlier findings demonstrating that signaling phosphatidylinositols regulate the NR5A receptors LRH-1 and SF-1.

KEYWORDS:

Crystal structure; LRH-1; Ligand; Liver Receptor Homolog-1; NR5A2; Nuclear receptor; PIP(3)

PMID:
26416531
PMCID:
PMC4651778
DOI:
10.1016/j.jsb.2015.09.012
[Indexed for MEDLINE]
Free PMC Article

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