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Figure 2.
Crystal structures of the EGFR T790M mutant show that
inhibitors are readily accommodated in the active and inactive
conformations of the kinase. (A) Superposition of EGFR
T790M/AEE788 complex (yellow) and WT/AEE788 complex [light blue;
drawn from PDB ID code 2J6M (8)]. Dashed lines indicate hydrogen
bonds to the kinase hinge region that are preserved in both
complexes. The location of the T790M mutation is indicated. (B)
Superposition of EGFR T790M/AEE788 complex (yellow) and
apo-T790M structure (green). Note the alternate side-chain
conformation of Met-790 in the presence of the inhibitor. (C)
Crystal structure of HKI-272 in complex with the T790M mutant.
The kinase adopts an inactive conformation, with the C-helix
displaced. A covalent bond is formed between Cys-797 and the
crotonamide Michael acceptor of HKI-272. (D) The structure of
the T790M mutant in complex with HKI-272 (yellow) is
superimposed on the structure of the WT EGFR kinase in complex
with Lapatinib [light blue; drawn from PDB ID code 1XKK (32)].
In both structures, the kinase adopts the same inactive
conformation and the inhibitors bind in a similar manner, with a
single hydrogen bond to the hinge (dashed lines) and with their
aniline substituents extending into the enlarged hydrophobic
pocket that is characteristic of the inactive conformation.
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