Dhar Gopa, Chakravarty Devlina, Hazra Joyita, Dhar Jesmita, Poddar Asim, Pal Mahadeb, Chakrabarti Pinak, Surolia Avadhesha, Bhattacharyya Bhabatarak
Department of Biochemistry, Bose Institute , Kolkata 700054, India.
Biochemistry. 2015 Feb 3;54(4):1132-43. doi: 10.1021/bi5014408. Epub 2015 Jan 17.
Curcumin, derived from rhizomes of the Curcuma longa plant, is known to possess a wide range of medicinal properties. We have examined the interaction of curcumin with actin and determined their binding and thermodynamic parameters using isothermal titration calorimetry. Curcumin is weakly fluorescent in aqueous solution, and binding to actin enhances fluorescence several fold with a large blue shift in the emission maximum. Curcumin inhibits microfilament formation, which is similar to its role in inhibiting microtubule formation. We synthesized a series of stable curcumin analogues to examine their affinity for actin and their ability to inhibit actin self-assembly. Results show that curcumin is a ligand with two symmetrical halves, each of which possesses no activity individually. Oxazole, pyrazole, and acetyl derivatives are less effective than curcumin at inhibiting actin self-assembly, whereas a benzylidiene derivative is more effective. Cell biology studies suggest that disorganization of the actin network leads to destabilization of filaments in the presence of curcumin. Molecular docking reveals that curcumin binds close to the cytochalasin binding site of actin. Further molecular dynamics studies reveal a possible allosteric effect in which curcumin binding at the "barbed end" of actin is transmitted to the "pointed end", where conformational changes disrupt interactions with the adjacent actin monomer to interrupt filament formation. Finally, the recognition and binding of actin by curcumin is yet another example of its unique ability to target multiple receptors.
姜黄素源自姜黄属植物的根茎，已知具有广泛的药用特性。我们研究了姜黄素与肌动蛋白的相互作用，并使用等温滴定量热法测定了它们的结合和热力学参数。姜黄素在水溶液中荧光较弱，与肌动蛋白结合会增强荧光数倍，且发射最大值有较大蓝移。姜黄素抑制微丝形成，这与其抑制微管形成的作用相似。我们合成了一系列稳定的姜黄素类似物，以研究它们对肌动蛋白的亲和力及其抑制肌动蛋白自组装的能力。结果表明，姜黄素是一种具有两个对称部分的配体，每个部分单独均无活性。恶唑、吡唑和乙酰基衍生物在抑制肌动蛋白自组装方面比姜黄素效果差，而亚苄基衍生物效果更好。细胞生物学研究表明，在存在姜黄素的情况下，肌动蛋白网络的紊乱会导致细丝不稳定。分子对接显示，姜黄素靠近肌动蛋白的细胞松弛素结合位点结合。进一步的分子动力学研究揭示了一种可能的变构效应，即姜黄素在肌动蛋白的“刺端”结合会传递到“尖端”，在那里构象变化会破坏与相邻肌动蛋白单体的相互作用，从而中断细丝形成。最后，姜黄素对肌动蛋白的识别和结合是其靶向多种受体独特能力的又一个例子。
