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Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants

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  • Sharad Verma
  • Sukriti Goyal
  • Anchala Kumari
  • Aditi Singh
  • Salma Jamal
  • Abhinav Grover

Abstract

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.

Suggested Citation

  • Sharad Verma & Sukriti Goyal & Anchala Kumari & Aditi Singh & Salma Jamal & Abhinav Grover, 2018. "Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants," PLOS ONE, Public Library of Science, vol. 13(2), pages 1-13, February.
    • Handle: RePEc:plo:pone00:0190942
    DOI: 10.1371/journal.pone.0190942
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    References listed on IDEAS

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    1. Sharad Verma & Sonam Grover & Chetna Tyagi & Sukriti Goyal & Salma Jamal & Aditi Singh & Abhinav Grover, 2016. "Hydrophobic Interactions Are a Key to MDM2 Inhibition by Polyphenols as Revealed by Molecular Dynamics Simulations and MM/PBSA Free Energy Calculations," PLOS ONE, Public Library of Science, vol. 11(2), pages 1-14, February.
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