Structure of the PPARα and -γ ligand binding domain in complex with AZ 242;: Ligand selectivity and agonist activation in the PPAR family
Structure of the PPARα and -γ ligand binding domain in complex with AZ 242;: Ligand selectivity and agonist activation in the PPAR family
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DOI：
10.1016/s0969-2126(01)00634-7
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发表时间：
2001-08-01
期刊：
影响因子：
5.7
通讯作者：
Bamberg, K
中科院分区：
文献类型：
--
作者：
Cronet, P;Petersen, JFW;Bamberg, K
背景资料：过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）是核受体家族中的一种配体激活的转录因子。已广泛表征了PPAR α在脂肪酸氧化中的作用和PPAR γ在脂肪细胞分化和脂质储存中的作用。PPARs被脂肪酸和类二十烷酸激活，也是抗血脂异常药物的靶点，但由于缺乏PPARalpha配体结合结构域，控制特定亚型配体选择性的分子相互作用尚不清楚。我们已经解决了与组合的PPAR α和-γ激动剂AZ 242复合的PPAR α配体结合结构域（LBD）的晶体结构，一种结构上不同于噻唑烷二酮的新的二氢肉桂酸酯衍生物。此外，我们提出了晶体结构的过氧化物酶体增殖物激活受体γ-LBD/AZ 242复合物，并提供了一个基本原理，对过氧化物酶体增殖物激活受体α和-γ亚型的配体选择性。在APO形式和与AZ 242复合的PPARa上的异源NMR数据显示在激动剂结合后LBD的总体稳定性。新的PPARalpha/AZ 242复合物与PPARgamma/AZ 242复合物和先前解决的PPARgamma结构的比较揭示了激动剂和AF 2 helix.Conclusions之间保守的氢键网络：PPARalpha和PPARgamma与双重特异性激动剂AZ 242的复合物突出了受体激活所需的保守相互作用。与NMR数据一起，这表明了PPAR家族中配体活化的一般模型。配体结合位点的比较揭示了亚型选择性的分子解释，并为合理的药物设计提供了基础。
Background: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPAR alpha in fatty acid oxidation and PPAR gamma in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPAR alpha ligand binding domain structure.Results: We have solved the crystal structure of the PPAR alpha ligand binding domain (LBD) in complex with the combined PPAR alpha and -gamma agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPAR gamma -LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPAR alpha and -gamma subtypes. Heteronuclear NMR data on PPARa in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPAR alpha /AZ 242 complex with the PPAR gamma /AZ 242 complex and previously solved PPAR gamma structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix.Conclusions: The complex of PPAR alpha and PPAR gamma with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design.