HER-2突变导致拉帕替尼耐药机制的结构研究
Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants.
作者信息
Verma Sharad, Goyal Sukriti, Kumari Anchala, Singh Aditi, Jamal Salma, Grover Abhinav
机构信息
School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, India.
出版信息
PLoS One. 2018 Feb 1;13(2):e0190942. doi: 10.1371/journal.pone.0190942. eCollection 2018.
HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant. Lapatinib showed stable but reverse orientation in binding site of K753E and the highest binding energy among studied HER2-lapatinib complexes but slightly lesser than L755S mutant. Results indicate that K753E has similar profile as L755S mutant for lapatinib. The interacting residues were also found different from other three studied forms as revealed by free energy decomposition and ligplot analysis.
HER-2属于人表皮生长因子受体（HER）家族。通过不同的信号转导途径，HER-2调节正常细胞的增殖、存活和分化。最近，有报道称携带HER2 K753E突变的MCF10A、BT474和MDA-MB-231细胞对拉帕替尼耐药。目前的研究表明，与野生型、L768S和V773L HER-2与拉帕替尼形成的复合物相比，HER-2突变体K753E表现出一些不同的行为，而与先前已知的对拉帕替尼耐药的L755S HER-2突变体相似。拉帕替尼在K753E的结合位点显示出稳定但相反的方向，并且在所研究的HER2-拉帕替尼复合物中具有最高的结合能，但略低于L755S突变体。结果表明，K753E与L755S突变体对拉帕替尼具有相似的特征。通过自由能分解和Ligplot分析发现，相互作用的残基也与其他三种研究形式不同。
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