Supplementary Fig.1 Comparison of the 3D structures of 2GS6 and 2GS7. A the superposed structures of 2GS6 (green) and 2GS7 (blue); B the enlarged image of the active centers of 2GS6 (up) and 2GS7 (down).

Supplementary Fig. 2 Defining the active center of EGFR mutants. A the superposed structures of the complexes of EGFR with Afatinib, Gefitinib, Osimiertinib or Erlotinib (PDB ID: 4G5J, 3UG2, 4ZAU, 1M17); B the superposition of EGFR-afatinib complex structure(PDBID:4G5J)and predicted structures of EGFREx19Del and EGFREx19Del+G724S. C enlarged image of B showing key amino acids of EGFR for drug binding.

Supplementary Fig.3 Comparison of Afatinib binding with EGFREx19Del and EGFREx19Del+G724S. A superposed structures of Afatinib+EGFREx19Del (green) and Afatinib+ EGFREx19Del+G724S (blue); B the enlarged view of active center of A; C the diagram of the interaction forces of Afatinib with EGFREx19Del; D the diagram of the interaction forces of Afatinib with EGFREx19Del+G724S.

Supplementary Fig.4 A Diagrams of molecular docking poses between Gefitinib and EGFR kinase domain mutants. Gefitinib+EGFREx19Del (green); Gefitinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Gefitinib with EGFREx19Del. D Diagrams of the interaction force of Gefitinib with EGFREx19Del+G724S.

Supplementary Fig.5 A Diagrams of molecular docking poses between Osimertinib and EGFR kinase domain mutants. Osimertinib+EGFREx19Del (green); Osimertinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Osimertinib with EGFREx19Del. D Diagrams of the interaction force of Osimertinib with EGFREx19Del+G724S.

Supplementary Fig.6 Comparison of Afatinib binding with EGFREx19Del and EGFREx19Del+G724S. A superposed structures of Afatinib+EGFREx19Del (green) and Afatinib+ EGFREx19Del+G724S (blue); B the enlarged view of active center of A; C the diagram of the interaction forces of Afatinib with EGFREx19Del; D the diagram of the interaction forces of Afatinib with EGFREx19Del+G724S.

Supplementary Fig.7 A Diagrams of molecular docking poses between Gefitinib and EGFR kinase domain mutants. Gefitinib+EGFREx19Del (green); Gefitinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Gefitinib with EGFREx19Del. D Diagrams of the interaction force of Gefitinib with EGFREx19Del+G724S.

Supplementary Fig.8 A Diagrams of molecular docking poses between Osimertinib and EGFR kinase domain mutants. Osimertinib+EGFREx19Del (green); Osimertinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Osimertinib with EGFREx19Del . D Diagrams of the interaction force of Osimertinib with EGFREx19Del+G724S.

Supplementary Fig.9 Comparison of Afatinib binding with EGFREx19Del and EGFREx19Del+G724S. A superposed structures of Afatinib+EGFREx19Del (green) and Afatinib+ EGFREx19Del+G724S (blue); B the enlarged view of active center of A; C the diagram of the interaction forces of Afatinib with EGFREx19Del; D the diagram of the interaction forces of Afatinib with EGFREx19Del+G724S.

Supplementary Fig.10 A Diagrams of molecular docking poses between Gefitinib and EGFR kinase domain mutants. Gefitinib+EGFREx19Del (green); Gefitinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Gefitinib with EGFREx19Del . D Diagrams of the interaction force of Gefitinib with EGFREx19Del+G724S.

Supplementary Fig.11 A Diagrams of molecular docking poses between Osimertinib and EGFR kinase domain mutants. Osimertinib+EGFREx19Del (green); Osimertinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Osimertinib with EGFREx19Del . D Diagrams of the interaction force of Osimertinib with EGFREx19Del+G724S.

Supplementary Fig.12 Comparison of Afatinib binding with EGFREx19Del and EGFREx19Del+G724S. A superposed structures of Afatinib+EGFREx19Del (green) and Afatinib+ EGFREx19Del+G724S (blue); B the enlarged view of active center of A; C the diagram of the interaction forces of Afatinib with EGFREx19Del; D the diagram of the interaction forces of Afatinib with EGFREx19Del+G724S.

Supplementary Fig.13 A Diagrams of molecular docking poses between Gefitinib and EGFR kinase domain mutants. Gefitinib+EGFREx19Del (green); Gefitinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Gefitinib with EGFREx19Del . D Diagrams of the interaction force of Gefitinib with EGFREx19Del+G724S.

Supplementary Fig.14 A Diagrams of molecular docking poses between Osimertinib and EGFR kinase domain mutants. Osimertinib+EGFREx19Del (green); Osimertinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Osimertinib with EGFREx19Del . D Diagrams of the interaction force of Osimertinib with EGFREx19Del+G724S.

Supplementary Fig.15 Comparison of Afatinib binding with EGFREx19Del and EGFREx19Del+G724S. A superposed structures of Afatinib+EGFREx19Del (green) and Afatinib+ EGFREx19Del+G724S (blue); B the enlarged view of active center of A; C the diagram of the interaction forces of Afatinib with EGFREx19Del; D the diagram of the interaction forces of Afatinib with EGFREx19Del+G724S.

Supplementary Fig.16 A Diagrams of molecular docking poses between Gefitinib and EGFR kinase domain mutants. Gefitinib+EGFREx19Del (green); Gefitinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Gefitinib with EGFREx19Del . D Diagrams of the interaction force of Gefitinib with EGFREx19Del+G724S.

Supplementary Fig.17 A Diagrams of molecular docking poses between Osimertinib and EGFR kinase domain mutants. Osimertinib+EGFREx19Del (green); Osimertinib+EGFREx19Del+G724S (blue). B the enlarged view of active center. C Diagrams of the interaction force of Osimertinib with EGFREx19Del . D Diagrams of the interaction force of Osimertinib with EGFREx19Del+G724S.