Spasevska Ivana, Ayoub Ahmed T, Winter Philip, Preto Jordane, Wong Gane K-S, Dumontet Charles, Tuszynski Jack A
INSERM 1052/CNRS 5286/UCBL, Cancer Center Research of Lyon, 69008 Lyon, France.
Medicinal Chemistry Department, Heliopolis University, Cairo-Belbeis Desert Rd, El-Nahda, El Salam, Cairo Governorate 11777, Egypt.
Int J Mol Sci. 2017 Aug 2;18(8):1676. doi: 10.3390/ijms18081676.
Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by . While produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine's cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in are investigated and compared to human tubulin. To this end, homology models for α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson-Boltzmann calculations (MM/PBSA) are performed to determine colchicine's binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by .
微管蛋白是许多小分子天然化合物的作用靶点，这些化合物会改变微管动力学，导致细胞周期停滞和细胞凋亡。其中一种化合物是秋水仙碱，一种由……产生的植物生物碱。虽然……产生一种强效细胞毒素秋水仙碱，并表达其靶蛋白，但它对秋水仙碱的细胞毒性作用具有抗性，且这种抗性机制迄今尚不清楚。在本文中，研究了……中对秋水仙碱抗性的分子机制，并与人类微管蛋白进行了比较。为此，构建了……α-β微管蛋白异二聚体的同源模型，并进行了分子动力学（MD）模拟以及分子力学泊松-玻尔兹曼计算（MM/PBSA），以确定秋水仙碱对微管蛋白的结合亲和力。使用我们的分子方法表明，与人类微管蛋白相比，……微管蛋白中的秋水仙碱结合位点含有少量氨基酸取代。然而，这些取代导致对微管蛋白的结合亲和力显著降低，随后其结构中的构象变化也较少。有人认为，这种微小的构象变化不足以深刻破坏微管动力学，这解释了……对秋水仙碱具有高度抗性的原因。
