Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C.
Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C.
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姜黄素及其长链衍生物与新型蛋白激酶 C 激活剂结合域的结合。
DOI：
10.1016/j.bmc.2009.12.075
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发表时间：
2010-02-15
影响因子：
3.5
通讯作者：
Das, Joydip
中科院分区：
文献类型：
--
作者：
Majhi, Anjoy;Rahman, Ghazi M.;Panchal, Shyam;Das, Joydip
蛋白激酶C(PKC)是一个丝氨酸/苏氨酸激酶家族，在细胞信号转导中发挥核心作用。具有两个长碳链的第二信使二酰甘油作为PKCs的内源性配体。姜黄素是姜黄中的活性成分，是一种抗癌活性物质，具有调节PKC活性的作用。为了开发姜黄素衍生物作为有效的蛋白激酶C激活剂，我们合成了几种姜黄素的长链衍生物，表征了它们的吸收和荧光性质，并研究了它们与激活剂结合的富含半胱氨酸的第二亚区PKCδ、PKCε和PKCθ的相互作用。姜黄素(1)及其C16长链类似物(4)对PKCδC1B、PKCεC1B和PKCθC1B的荧光猝灭作用类似于PKC激活剂12-O-十四酰佛波醇13-醋酸酯(TPA)。姜黄素衍生物用于荧光猝灭的EC50在4~11μM范围内变化，对苯丙氨酸的EC50在3~6μM范围内变化，在C1B结构域的存在下，荧光发射最大值1和4发生蓝移，荧光各向异性值增加，证实它们与蛋白质结合。1和4与新型PKC C1B的分子对接表明，这两个分子都与蛋白质残基形成了氢键。结果表明，姜黄素及其长链衍生物可与新型PKCs的C1B亚区结合，并可通过进一步的结构修饰来提高其结合力和活性。
Protein Kinase C (PKC) is a family of serine/threonine kinases that play a central role in cellular signal transduction. The second messenger diacylglycerol having two long carbon chains acts as the endogenous ligand for the PKCs. Polyphenol curcumin, the active constituent of Curcuma longa is an anticancer agent and modulates PKC activity. To develop curcumin derivatives as effective PKC activators, we synthesized several long chain derivatives of curcumin, characterized their absorption and fluorescence properties and studied their interaction with the activator-binding second cysteine-rich C1B subdomain of PKCδ, PKCε and PKCθ. Curcumin (1) and its C16 long chain analog (4) quenched the intrinsic fluorescence of PKCδC1B, PKCεC1B and PKCθC1B in a manner similar to that of PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA). The EC50s of the curcumin derivatives for fluorescence quenching varied in the range of 4-11 μM, whereas, EC50s for TPA varied in the range of 3-6 μM. Fluorescence emission maxima of 1 and 4 were blue shifted and the fluorescence anisotropy values were increased in the presence of the C1B domains similar to that shown by the fluorescent analog of TPA, sapintoxin–D, confirming that they were bound to the proteins. Molecular docking of 1 and 4 with novel PKC C1B revealed that both the molecules form hydrogen bonds with the protein residues. The present result shows that curcumin and its long chain derivatives bind to the C1B subdomain of novel PKCs and can be further modified structurally to improve its binding and activity.
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影响因子：
7.3
作者：
af Gennas, Gustav Boije;Talman, Virpi;Yli-Kauhaluoma, Jari
通讯作者：
Yli-Kauhaluoma, Jari
影响因子：
3.6
作者：
Choi, Hyunsung;Chun, Yang-Sook;Park, Jong-Wan
通讯作者：
Park, Jong-Wan
影响因子：
4.8
作者：
Das, J;Addona, GH;Miller, KW
通讯作者：
Miller, KW
影响因子：
4.1
作者：
Das, Joydip;Pany, Satyabrata;Slater, Simon J.
通讯作者：
Slater, Simon J.
影响因子：
8
作者：
Das, Joydip;Zhou, Xiaojuan;Miller, Keith W.
通讯作者：
Miller, Keith W.