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Molecular recognition of nitrated fatty acids by PPARγ

Nature Structural & Molecular Biology volume 15, pages 865867 (2008) | Download Citation

Abstract

Peroxisome proliferator activated receptor-γ (PPARγ) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPARγ ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPARγ. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPARγ discrimination of various naturally occurring fatty acid derivatives.

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Acknowledgements

We thank W.D. Tolbert and Z. Wawrzak for assistance in data collection at the DND-CAT of the Advanced Photon Source. Use of the Advanced Photon Source was supported by the US Office of Science of the US Department of Energy. This work was supported in part by the Jay and Betty Van Andel Foundation (H.E.X.), US National Institutes of Health Grants DK071662 and DK066202 (H.E.X.), HL089301 (H.E.X. and Y.L.), HL68878, HL089544 and HL75397 (Y.E.C.), HL58115 and HL64937 (B.A.F.), American Diabetes Association (P.R.S.B.) and awards from the American Heart Association (Y.L., F.J.S.).

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Affiliations

  1. Department of Pharmaceutical Sciences, Center for Pharmacogenetics, 709 Salk Hall, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

    • Yong Li
    •  & Dariusz Martynowski
  2. Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.

    • Yong Li
    • , Amanda Kovach
    • , Kelly Suino-Powell
    •  & H Eric Xu
  3. Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA.

    • Jifeng Zhang
    •  & Y Eugene Chen
  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

    • Francisco J Schopfer
    • , Paul R S Baker
    •  & Bruce A Freeman
  5. Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, Georgia 30310, USA.

    • Minerva T Garcia-Barrio

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Corresponding authors

Correspondence to Yong Li or H Eric Xu.

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    Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Methods

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DOI

https://doi.org/10.1038/nsmb.1447

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