1. Department of Structural Chemistry, North Carolina 27709, USA
2. Department of Medicinal Chemistry, Division of Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA
3. Division of Cellular and Molecular Medicine, San Diego, La Jolla, California 92093-0651, USA
4. Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0651, USA
5. These authors contributed equally to this work

Correspondence to: Michael V. Milburn¹ Correspondence and requests for materials should be addressed to M.V.M. (e-mail: Email: mvm25452@glaxowellcome.com).Coordinates for the apo-PPAR- (1PRG) and the PPAR–rosiglitazone–SRC1 ternary complex (2PRG) have been deposited with the Brookhaven Protein Database.

Abstract

The peroxisome proliferator-activated receptor- (PPAR-) 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- 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-. We also describe the ternary complex containing the PPAR- 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- homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.