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PDBsum entry 3vjn
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References listed in PDB file
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Key reference
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Title
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Structural basis for the altered drug sensitivities of non-Small cell lung cancer-Associated mutants of human epidermal growth factor receptor.
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Authors
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S.Yoshikawa,
M.Kukimoto-Niino,
L.Parker,
N.Handa,
T.Terada,
T.Fujimoto,
Y.Terazawa,
M.Wakiyama,
M.Sato,
S.Sano,
T.Kobayashi,
T.Tanaka,
L.Chen,
Z.J.Liu,
B.C.Wang,
M.Shirouzu,
S.Kawa,
K.Semba,
T.Yamamoto,
S.Yokoyama.
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Ref.
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Oncogene, 2013,
32,
27-38.
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PubMed id
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Abstract
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The epidermal growth factor receptor (EGFR) has an essential role in multiple
signaling pathways, including cell proliferation and migration, through
extracellular ligand binding and subsequent activation of its intracellular
tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated
EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They
display sensitivity to TK inhibitors, including gefitinib and erlotinib. In
contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly
confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our
biochemical analyses revealed that the introduction of the T790M mutation
confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant
has enhanced activity and retains high gefitinib-binding affinity. The T790M
mutation increases the ATP affinity of the G719S mutant, explaining the acquired
drug resistance of the double mutant. Structural analyses of the G719S/T790M
double mutant, as well as the wild type and the G719S and L858R mutants,
revealed that the T790M mutation stabilizes the hydrophobic spine of the active
EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in
the apo form and gefitinib- and AMPPNP-bound forms, adopts different
conformations that explain the accommodation of these ligands. In the L858R
mutant structure, the active-site cleft is expanded by the repositioning of
Phe723 within the P-loop. Notably, the introduction of the F723A mutation
greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo,
supporting our hypothesis that the expansion of the active-site cleft results in
enhanced gefitinib sensitivity. Taken together, our results provide a structural
basis for the altered drug sensitivities caused by distinct NSCLC-associated
EGFR mutations.
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