Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein
Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein
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DOI：
10.1007/s00249-010-0608-9
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发表时间：
2010-10-01
影响因子：
2
通讯作者：
Stote, Roland H.
中科院分区：
文献类型：
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作者：
Fidelak, Jeremy;Ferrer, Silvia;Stote, Roland H.
过氧化物酶体增殖物激活受体-γ核受体（PPAR-γ）属于核受体蛋白超家族，作为配体依赖性转录因子发挥作用，并作为脂质代谢调节剂发挥特定的生理作用。许多实验研究表明变构在 PPAR-gamma 的功能中发挥着重要作用。在这里，我们使用 PPAR-gamma 的正常模式分析来表征动态耦合氨基酸网络，该网络将生理相关的结合表面（例如配体依赖性激活结构域 AF-2）与配体结合位点和异二聚体界面连接起来。在存在和不存在激动剂罗格列酮的情况下进行了多次计算，并表征了动力学差异。配体结合结构域的整体动态受到配体的影响，特别是，观察到动态相关氨基酸网络的变化，而构象仅发生微小变化。这些结果表明，动态耦合的变化对于变构信号的传递可能具有重要的功能。
Peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-gamma) belongs to the superfamily of nuclear receptor proteins that function as ligand-dependent transcription factors and plays a specific physiological role as a regulator of lipid metabolism. A number of experimental studies have suggested that allostery plays an important role in the functioning of PPAR-gamma. Here we use normal-mode analysis of PPAR-gamma to characterize a network of dynamically coupled amino acids that link physiologically relevant binding surfaces such as the ligand-dependent activation domain AF-2 with the ligand binding site and the heterodimer interface. Multiple calculations were done in both the presence and absence of the agonist rosiglitazone, and the differences in dynamics were characterized. The global dynamics of the ligand binding domain were affected by the ligand, and in particular, changes to the network of dynamically correlated amino acids were observed with only small changes in conformation. These results suggest that changes in dynamic couplings can be functionally significant with respect to the transmission of allosteric signals.