Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
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DOI：
10.1038/25931
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发表时间：
1998-09-10
期刊：
影响因子：
64.8
通讯作者：
Milburn, MV
中科院分区：
文献类型：
--
作者：
Nolte, RT;Wisely, GB;Milburn, MV
过氧化物酶体增殖物激活受体-γ(PPAR-γ)是一种配体依赖的转录因子，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)在内的共激活剂的相互作用。这种结构揭示了一个大的结合口袋，这可以解释PPAR-伽马的配体的多样性。我们还描述了包含PPAR-伽马LED、抗糖尿病配体罗格列酮(BRL49653)和人SRC-1的88个氨基酸的三元络合物，分辨率为2.3埃。在核受体的LBD中高度保守的谷氨酸和赖氨酸残基形成了一个“电荷钳”，与SRC-1的LxxL1螺旋的主干原子联系。这些结果，再加上SRC-1的两个连续的LxxLL基序与PPAR-γ同源二聚体的两个亚基进行完全相同的接触的观察，表明了核受体与共激活剂组装的一般机制。
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 Angstrom 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 LED, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 Angstrom 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.