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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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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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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DOI: https://doi.org/10.1038/25931
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