Figure 4.
The experimental electron densities of EGFR and c-Src-cys at
2.95 Å and 2.48 Å resolution, respectively, are
shown (2F[o] – F[c] map contoured at 1 ).
(a) Optimized EGFR inhibitor 2 (PD 168393)^13 (green ball and
sticks) in complex with the EGFR kinase domain shows clear
electron density between the targeted Cys797 and the acrylamide
Michael acceptor on 2. The inhibitor makes a direct hydrogen
bond between its quinazoline N1 and the main chain amide of
Met793, which is a common recognition motif among reversible
anilinoquinazolines and several protein kinase domains^16, ^20,
^21, ^22, ^23, ^24. We find the cocrystal complex in an active
conformation of EGFR: a conserved salt bridge found only in
active EGFR conformations between the catalytic Lys745 and helix
C Glu762 remains intact. The m-bromine group sits adjacent
(within 3.4 Å) to the gatekeeper residue, Thr790. (b)
Notably, structures of 2 in complex with c-Src-cys show an
inhibitor binding mode distinct from any reported for
anilinoquinazolines with a protein kinase. In molecule B of the
c-Src-cys–2 complex, 2 (green ball and sticks) forms a
water-mediated (W1) hydrogen bond via its N1 of the quinazoline
core to the backbone amide of Met341.
).
(a) Optimized EGFR inhibitor 2 (PD 168393)^13 (green ball and
sticks) in complex with the EGFR kinase domain shows clear
electron density between the targeted Cys797 and the acrylamide
Michael acceptor on 2. The inhibitor makes a direct hydrogen
bond between its quinazoline N1 and the main chain amide of
Met793, which is a common recognition motif among reversible
anilinoquinazolines and several protein kinase domains^16, ^20,
^21, ^22, ^23, ^24. We find the cocrystal complex in an active
conformation of EGFR: a conserved salt bridge found only in
active EGFR conformations between the catalytic Lys745 and helix
C Glu762 remains intact. The m-bromine group sits adjacent
(within 3.4 Å) to the gatekeeper residue, Thr790. (b)
Notably, structures of 2 in complex with c-Src-cys show an
inhibitor binding mode distinct from any reported for
anilinoquinazolines with a protein kinase. In molecule B of the
c-Src-cys–2 complex, 2 (green ball and sticks) forms a
water-mediated (W1) hydrogen bond via its N1 of the quinazoline
core to the backbone amide of Met341.