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

Robert T. Nolte, G. Bruce Wisely, Stefan Westin, Jeffery E. Cobb, Millard H. Lambert, Riki Kurokawa, Michael G. Rosenfeld, Timothy M. Willson, Christopher K. Glass and Michael V. Milburn ()
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Robert T. Nolte: Department of Structural Chemistry
G. Bruce Wisely: Department of Structural Chemistry
Stefan Westin: San Diego
Jeffery E. Cobb: Glaxo Wellcome Research and Development, Research Triangle Park
Millard H. Lambert: Department of Structural Chemistry
Riki Kurokawa: San Diego
Michael G. Rosenfeld: Howard Hughes Medical Institute, University of California, San Diego
Timothy M. Willson: Glaxo Wellcome Research and Development, Research Triangle Park
Christopher K. Glass: San Diego
Michael V. Milburn: Department of Structural Chemistry

Nature, 1998, vol. 395, issue 6698, 137-143

Abstract: 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.

Date: 1998
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DOI: 10.1038/25931

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