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
Department of Structural Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Nature. 1998 Sep 10;395(6698):137-43. doi: 10.1038/25931.
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.
过氧化物酶体增殖物激活受体γ（PPAR-γ）是一种依赖配体的转录因子，在脂肪细胞分化和葡萄糖稳态中起重要作用，它依赖于与包括类固醇受体共激活因子-1（SRC-1）在内的共激活因子相互作用。在此，我们展示了分辨率为2.2埃的人无配体PPAR-γ配体结合域（LBD）的X射线晶体结构；该结构揭示了一个大的结合口袋，这可能解释了PPAR-γ配体的多样性。我们还描述了分辨率为2.3埃的包含PPAR-γ LBD、抗糖尿病配体罗格列酮（BRL49653）和人SRC-1的88个氨基酸的三元复合物。在核受体LBD中高度保守的谷氨酸和赖氨酸残基形成一个“电荷钳”，与SRC-1的LXXLL螺旋的主链原子接触。这些结果，连同观察到SRC-1的两个连续LXXLL基序与PPAR-γ同二聚体的两个亚基进行相同接触，提示了核受体与共激活因子组装的一般机制。
