Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.
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.
Nolte
R T
RT
Department of Structural Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Wisely
G B
GB
Westin
S
S
Cobb
J E
JE
Lambert
M H
MH
Kurokawa
R
R
Rosenfeld
M G
MG
Willson
T M
TM
Glass
C K
CK
Milburn
M V
MV
D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D051548:Histone Acetyltransferases; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation
D007004:Hypoglycemic Agents; D008024:Ligands; D046911:Macromolecular Substances; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1