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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Diabetes Mellitus / genetics
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Diabetes Mellitus / metabolism
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Gene Expression Regulation*
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Humans
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Hypoglycemic Agents / metabolism*
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Molecular Dynamics Simulation
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Nuclear Receptor Co-Repressor 2 / metabolism
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Nuclear Receptor Coactivator 2 / chemistry
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Nuclear Receptor Coactivator 2 / metabolism
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Phosphatidylcholines / genetics
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Phosphatidylcholines / metabolism*
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Protein Binding
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Protein Structure, Secondary
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
Substances
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Hypoglycemic Agents
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NCOA2 protein, human
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NCOR2 protein, human
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NR5A2 protein, human
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Nuclear Receptor Co-Repressor 2
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Nuclear Receptor Coactivator 2
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Phosphatidylcholines
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Receptors, Cytoplasmic and Nuclear
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nuclear receptor subfamily 0, group B, member 2
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1,2-dilauroylphosphatidylcholine