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Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ

Nature volume 395, pages 137–143 (1998)Cite this article

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1). Here we present the X-ray crystal structure of the human apo-PPAR-γ ligand-binding domain (LBD), at 2.2 Å resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-γ. We also describe the ternary complex containing the PPAR-γ LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 Å resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a ‘charge clamp’ that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-γ homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.

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Figure 1: Crystal structure of the apo-PPAR-γ.
Figure 2: Rosiglitazone binding with the PPAR-γ LBD and SRC-1 in the ternary complex.
Figure 3: SRC-1 interactions with PPAR-γ.

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Acknowledgements

We thank W. Burkhart, M. Moyer and K. Blackburn for protein sequencing and mass spectrometry; S. Blanchard, P. Charifson, T. Consler, S. Jordan, S. Kliewer, J. Lehmann, C. Mohr and E. Xu for discussions; A. Miller for artwork; and K. Milburn for computational assistance.

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Author notes

  1. Robert T. Nolte, G. Bruce Wisely and Michael G. Rosenfeld: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Structural Chemistry, North Carolina, 27709, USA

    Robert T. Nolte, G. Bruce Wisely, Millard H. Lambert & Michael V. Milburn

  2. Department of Medicinal Chemistry, Division of Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina, 27709, USA

    Jeffery E. Cobb & Timothy M. Willson

  3. Division of Cellular and Molecular Medicine, San Diego, La Jolla, 92093-0651, California, USA

    Stefan Westin, Riki Kurokawa & Christopher K. Glass

  4. Department of Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, 92093-0651, California, USA

    Michael G. Rosenfeld

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Correspondence to Michael V. Milburn.

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Nolte, R., Wisely, G., Westin, S. et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 395, 137–143 (1998). https://doi.org/10.1038/25931

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