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- Title
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.
- Authors
Nolte, R T; Wisely, G B; Westin, S; Cobb, J E; Lambert, M H; Kurokawa, R; Rosenfeld, M G; Willson, T M; Glass, C K; Milburn, M V
- Abstract
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 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-gamma ligand-binding domain (LBD), at 2.2 A resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma. We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A 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-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.
- Publication
Nature, 1998, Vol 395, Issue 6698, p137
- ISSN
0028-0836
- Publication type
Journal Article
- DOI
10.1038/25931