TY - JOUR
T1 - Structural insight into the binding mechanism of ATP to EGFR and L858R, and T790M and L858R/T790 mutants
AU - Saldaña-Rivera, Lucia
AU - Bello, Martiniano
AU - Méndez-Luna, David
N1 - Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2019/11/22
Y1 - 2019/11/22
N2 - The L858R mutation in EGFR is particularly responsive to small tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. This efficacy decreases due to drug resistance conferred by a second mutation, T790M, which subsequently produces a double mutant, L858R/T790M. Although this resistance was initially attributed to steric blocking by the T790M mutation, experimental studies have demonstrated that differences in the binding affinities of TKIs to T790M and L858R/T790M mutants are more a result of the increased sensitivity of these mutants to ATP than to a decrease in the affinity to TKIs. Regrettably, detailed information at the atomic level on the origins of the increased binding affinity of mutants for ATP is lacking. In this study, we have combined structural data and molecular dynamics simulations with the MMGBSA approach to determine how the L858R, T790M and L858R/T790 mutations impact the binding mechanism of ATP with respect to wild-type EGFR. Structural and energetic analyses provided novel information that helps to explain the increased affinity of ATP to T790M and L858R/T790 mutants with respect to L858R and wild-type systems. In addition, it was observed that dimerization of the wild-type and mutant systems exerts dissimilar effects on the ATP binding affinity characteristic of negative cooperativity. Communicated by Ramaswamy H. Sarma.
AB - The L858R mutation in EGFR is particularly responsive to small tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. This efficacy decreases due to drug resistance conferred by a second mutation, T790M, which subsequently produces a double mutant, L858R/T790M. Although this resistance was initially attributed to steric blocking by the T790M mutation, experimental studies have demonstrated that differences in the binding affinities of TKIs to T790M and L858R/T790M mutants are more a result of the increased sensitivity of these mutants to ATP than to a decrease in the affinity to TKIs. Regrettably, detailed information at the atomic level on the origins of the increased binding affinity of mutants for ATP is lacking. In this study, we have combined structural data and molecular dynamics simulations with the MMGBSA approach to determine how the L858R, T790M and L858R/T790 mutations impact the binding mechanism of ATP with respect to wild-type EGFR. Structural and energetic analyses provided novel information that helps to explain the increased affinity of ATP to T790M and L858R/T790 mutants with respect to L858R and wild-type systems. In addition, it was observed that dimerization of the wild-type and mutant systems exerts dissimilar effects on the ATP binding affinity characteristic of negative cooperativity. Communicated by Ramaswamy H. Sarma.
KW - ATP
KW - Epidermal growth factor receptor
KW - binding free energy
KW - molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=85060009138&partnerID=8YFLogxK
U2 - 10.1080/07391102.2018.1558112
DO - 10.1080/07391102.2018.1558112
M3 - Artículo
C2 - 30558477
SN - 0739-1102
VL - 37
SP - 4671
EP - 4684
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 17
ER -