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

Academic Article
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Overview

authors

  • Musille, P. M.
  • Pathak, M. C.
  • Lauer, J. L.
  • Hudson, W. H.
  • Griffin, Patrick
  • Ortlund, E. A.

publication date

  • May 2012

journal

  • Nature Structural & Molecular Biology  Journal

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.

subject areas

  • Crystallography, X-Ray
  • Diabetes Mellitus
  • Gene Expression Regulation
  • Humans
  • Hypoglycemic Agents
  • Molecular Dynamics Simulation
  • Nuclear Receptor Co-Repressor 2
  • Nuclear Receptor Coactivator 2
  • Phosphatidylcholines
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Cytoplasmic and Nuclear
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Identity

PubMed Central ID

  • PMC3960984

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb.2279

PubMed ID

  • 22504882
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Additional Document Info

start page

  • 532

end page

  • 7, S1

volume

  • 19

issue

  • 5

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