Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines
Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines
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DOI：
10.3389/fmolb.2019.00159
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发表时间：
2020-01-24
影响因子：
5
通讯作者：
Wei, Dong-Qing
中科院分区：
文献类型：
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作者：
Khan, Abbas;Ashfaq-Ur-Rehman;Wei, Dong-Qing
乳腺癌（BC）的发病率每天都在上升，已被证明是发达国家和发展中国家妇女最常见的死亡原因。在绝经后诊断的所有BC病例中，70%的病例为雌激素受体（ER）阳性（ER阳性或ER+）。ER的LBD（配体结合结构域）突变最近被报道是对强效拮抗剂耐药的主要原因。在本研究中，分析了实验报告的突变K303R、E380Q、V392I、S463P、V524E、P535H、P536H、Y537C、Y537N、Y537S和D538G，并基于多重分析入围最显著的突变。初始分析，如mCSM稳定性、闭塞深度分析、mCSM结合亲和力和FoldX能量变化，仅将6个突变列入高耐药候选名单。最后，对6种mER α变体（E380 Q、S463 P、Y537 S、Y537 C、Y537 N和D538 G）进行了基于力场的分子动力学模拟（野生型（WT）ER α的MD），以证明耐药机制。据观察，这些突变增加了H12的灵活性。键合分析表明，以前报道的重要残基His524突变后失去键合。其他参数，如PCA（主成分分析），DCCM（动力学互相关），和FEL（自由能景观），验证了入围的突变影响H12螺旋，这打开了辅激活剂结合构象。这些结果为深入了解乳腺癌突变导致的氟维司群相对耐药机制提供了依据。这项研究将有助于进一步了解设计具体和更有效的药物的重要方面。
Incidents of breast cancer (BC) are on the rise on a daily basis and have proven to be the most prevelant cause of death for women in both developed and developing countries. Among total BC cases diagnosed after menopause, 70% of cases are Estrogen Receptor (ER) positive (ER-positive or ER+). Mutations in the LBD (ligand-binding domain) of the ER have recently been reported to be the major cause of resistance to potent antagonists. In this study, the experimentally reported mutations K303R, E380Q, V392I, S463P, V524E, P535H, P536H, Y537C, Y537N, Y537S, and D538G were analyzed, and the most significant mutations were shortlisted based on multiple analyses. Initial analyses, such as mCSM stability, occluded depth analysis, mCSM-binding affinity, and FoldX energy changes shortlisted only six mutations as being highly resistant. Finally, simulations of force field-based molecular dynamics (MD on wild type (WT) ER alpha) on six mER alpha variants (E380Q, S463P, Y537S, Y537C, Y537N, and D538G) were carried out to justify mechanism of the resistance. It was observed that these mutations increased the flexibility of the H12. A bonding analysis suggested that previously reported important residue His524 lost bonding upon mutation. Other parameters, such as PCA (principal component analysis), DCCM (dynamics cross-correlation), and FEL (free energy landscape), verified that the shortlisted mutations affect the H12 helix, which opens up the co-activator binding conformation. These results provide deep insight into the mechanism of relative resistance posed to fulvestrant due to mutations in breast cancer. This study will facilitate further understanding of the important aspects of designing specific and more effective drugs.