期刊
JOURNAL OF STRUCTURAL BIOLOGY
卷 192, 期 3, 页码 342-348出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2015.09.012
关键词
Nuclear receptor; Liver Receptor Homolog-1; LRH-1; NR5A2; Crystal structure; PIP3; Ligand
资金
- National Institute of General Medical Sciences (NIGMS) Fellowship [K12GM081266, 1K01CA172957, R01DK078075]
- Department of Defense [W81XWH-12-1-0396]
- Protein Structure Initiative (PSI) Grant, PSI-Biology Partnership for Stem Cell Biology [U01 GM094614]
- NIGMS, PSI [U54 GM094586]
- U.S. Department of Energy (DOE)
- Office of Science
- Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- [R01DK072246]
- [R01DK099722]
- [P41 GM103393]
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)P-2 (PIP2) and PI(3,4,5)P-3 (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. Published by Elsevier Inc.
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