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PDBsum entry 2oiq
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References listed in PDB file
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Key reference
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Title
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C-Src binds to the cancer drug imatinib with an inactive abl/c-Kit conformation and a distributed thermodynamic penalty.
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Authors
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M.A.Seeliger,
B.Nagar,
F.Frank,
X.Cao,
M.N.Henderson,
J.Kuriyan.
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Ref.
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Structure, 2007,
15,
299-311.
[DOI no: ]
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PubMed id
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Abstract
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The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the
PDGF receptor. Imatinib is less effective against c-Src, which is difficult to
understand because residues interacting with imatinib in crystal structures of
Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase
domain in complex with imatinib closely resembles that of Abl*imatinib and
c-Kit*imatinib, and differs significantly from the inactive "Src/CDK"
conformation of the Src family kinases. Attempts to increase the affinity of
c-Src for imatinib by swapping residues with the corresponding residues in Abl
have not been successful, suggesting that the thermodynamic penalty for adoption
of the imatinib-binding conformation by c-Src is distributed over a broad region
of the structure. Two mutations that are expected to destabilize the inactive
Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the
free-energy balance between different inactive states is a key to imatinib
binding.
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Figure 1.
Figure 1. The Imatinib-Binding Pocket
(A) Chemical
structure of imatinib.
(B) The imatinib-binding pocket in
Abl (PDB code 1OPJ) (Nagar et al., 2003). The Cα atoms of
residues that interact with imatinib are depicted as spheres.
Blue, residues that are invariant among Abl, c-Src, Lck, Hck,
PDGFR, and c-Kit; yellow, residues that are identical between
Abl and c-Src, but not between Abl and c-Kit or PDGFR; red,
residues unique to Abl.
(C) Sequence alignment of Abl,
c-Src, Hck, Lck, PDGFR, and c-Kit kinase domains. Residues that
are the same as in Abl are yellow. Residues that interact with
imatinib in the structure of Abl are in orange. Stars are color
coded according to the spheres in (B).
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Figure 7.
Figure 7. Comparison of Imatinib-Bound Structures
(A)
Structure of c-Src•imatinib (this work, PDB code 2OIQ). The
activation loop is disordered from residue 408 to residue 420,
and the phosphate-binding P loop is extended, leaving the
phenylalanine side chain solvent exposed.
(B) Structure of
Abl•imatinib (PDB code 1OPJ [Nagar et al., 2002]). The
phosphate-binding loop is kinked toward the C lobe of the
kinase, allowing for hydrogen bonds between Tyr253 and Asn322
(not shown).
(C) Structure of c-Kit•imatinib (PDB code
1T46 [Mol et al., 2004]). The phosphate-binding loop is
extended, as seen in the structure of c-Src, and Phe600 is
solvent exposed.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2007,
15,
299-311)
copyright 2007.
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