Pathological role of a point mutation (T315I) in BCR-ABL1 proteinA computational insight
Pathological role of a point mutation (T315I) in BCR-ABL1 proteinA computational insight
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DOI：
10.1002/jcb.26257
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Sethumadhavan, Rao
中科院分区：
文献类型：
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作者：
Rajendran, Vidya;Gopalakrishnan, Chandrasekhar;Sethumadhavan, Rao
BCR-ABL蛋白是治疗慢性粒细胞白血病（CML）最有效的靶点之一。除了其他突变之外，T315 I尤其具有挑战性，因为它赋予对所有第一代和第二代酪氨酸激酶抑制剂的抗性。因此，对突变后改变的行为进行彻底的研究是至关重要的。为了了解突变BCR-ABL蛋白的抗性机制，我们组织了一个长期的分子动力学模拟（500 ns），并进行了详细的比较构象分析。我们发现，由于第315位的突变（苏氨酸突变为异亮氨酸），原始结构偏离正常，并获得柔性构象。我们的观察为设计针对耐药BCR-ABL 1蛋白的新抑制剂铺平了一条明确的道路，并提出了一种策略，其中可以适当考虑由突变控制的额外灵活性。
BCR-ABL protein is one of the most potent target to treat chronic myeloid leukemia (CML). Apart from other mutations, T315I is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. So, a thorough study of altered behavior upon mutation is crucially needed. To understand the resistance mechanism of mutant BCR-ABL protein, we organized a long-term molecular dynamics simulation (500ns) and performed the detailed comparative conformational analysis. We found that due to mutation at 315th position (threonine to isoleucine), original structures deviated from normal, and attained a flexible conformation. Our observations pave a clear path toward designing new inhibitors against resistant BCR-ABL1 protein and suggest a strategy where additional flexibility governed by mutation could be given an appropriate consideration.