Conformational Transitions in EGFR Protein Tyrosine Kinase Domain and Their Modulation by Mutants

The epidermal growth factor receptor (EGFR) is a membrane protein with intracellular kinase activity. The EGFR plays a significant role in the cell signalling pathway that regulates cell division and survival of the cell. Mutations in the EGFR gene cause elevated activity of EGFR protein, resulting in cancer. Several mutations have been reported in the tyrosine kinase (TK) domain of the EGFR protein. This study aims to determine the conformational changes caused due to mutations in the active TK domain. The structure of 44 mutants and wild type were predicted using homology and ab-initio modelling techniques. The overall quality of generated protein structures was good with an average confidence score of 0.37. The predicted structures were subjected to structure quality analysis with an average Z-score (− 7.38) lying in the NMR region and similar to that of the wild type. An average of 85.72% residues were observed in the most favourable regions for all mutants with Mutant 30 (D770_N771insGF) showing the least of 74.7% and Mutant 17 (R748_S752del) showing the highest of 90% residues in the most favourable region. Deviations between wild type and mutants were observed using structural alignment to determine changes in the active site region. Mutant 12 (K745_E746delinsIPVAIK) exhibited the highest deviation (15.9), whereas Mutant 21 (T790M) had the least deviation of 0.1 Angstrom. The effect of these mutations on the structural conformations of the EGFR active tyrosine kinase domain may help in designing new efficient inhibitors for EGFR mutants.