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Title: Antidiabetic phospholipid-nuclear receptor complex reveals the mechanism for phospholipid-driven gene regulation.

Authors: Musille, Paul M; Pathak, Manish; Lauer, Janelle L; Hudson, William H; Griffin, Patrick R; Ortlund, Eric A

Published In Nat Struct Mol Biol, (2012 Apr 15)

Abstract: The human nuclear receptor liver receptor homolog-1 (LRH-1) has an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of diabetes and hepatic diseases. LRH-1 is known to bind phospholipids, but the role of phospholipids in controlling LRH-1 activation remains highly debated. Here we describe the structure of both apo LRH-1 and LRH-1 in complex with the antidiabetic phospholipid dilauroylphosphatidylcholine (DLPC). Together with hydrogen-deuterium exchange MS and functional data, our studies show that DLPC binding is a dynamic process that alters co-regulator selectivity. We show that the lipid-free receptor undergoes previously unrecognized structural fluctuations, allowing it to interact with widely expressed co-repressors. These observations enhance our understanding of LRH-1 regulation and highlight its importance as a new therapeutic target for controlling diabetes.

PubMed ID: 22504882 Exiting the NIEHS site

MeSH Terms: Crystallography, X-Ray; Diabetes Mellitus/genetics; Diabetes Mellitus/metabolism; Gene Expression Regulation*; Humans; Hypoglycemic Agents/metabolism*; Molecular Dynamics Simulation; Nuclear Receptor Co-Repressor 2/metabolism; Nuclear Receptor Coactivator 2/chemistry; Nuclear Receptor Coactivator 2/metabolism; Phosphatidylcholines/genetics; Phosphatidylcholines/metabolism*; Protein Binding; Protein Structure, Secondary; Receptors, Cytoplasmic and Nuclear/chemistry; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism*

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