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PDBsum entry 2pl0
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References listed in PDB file
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Key reference
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Title
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Classifying protein kinase structures guides use of ligand-Selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
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Authors
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M.D.Jacobs,
P.R.Caron,
B.J.Hare.
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Ref.
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Proteins, 2008,
70,
1451-1460.
[DOI no: ]
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PubMed id
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Abstract
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We report a clustering of public human protein kinase structures based on the
conformations of two structural elements, the activation segment and the
C-helix, revealing three discrete clusters. One cluster includes kinases in
catalytically active conformations. Each of the other clusters contains a
distinct inactive conformation. Typically, kinases adopt at most one of the
inactive conformations in available X-ray structures, implying that one of the
conformations is preferred for many kinases. The classification is consistent
with selectivity profiles of several well-characterized kinase inhibitors. We
show further that inhibitor selectivity profiles guide kinase classification.
For example, selective inhibition of lck among src-family kinases by imatinib
(Gleevec) suggests that the relative stabilities of inactive conformations of
lck are different from other src-family kinases. We report the X-ray structure
of the lck/imatinib complex, confirming that the conformation adopted by lck is
distinct from other structurally-characterized src-family kinases and instead
resembles kinases abl1 and kit in complex with imatinib. Our classification
creates new paths for designing small-molecule inhibitors.
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Figure 5.
Figure 5. Lck/imatinib complex. Comparison of X-ray structures
of lck/imatinib (green) and abl/imatinib (gray) complexes. The
side chains of the Asp and Phe residues in the conserved DFG
motif are shown.
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Figure 6.
Figure 6. Overlay of lck/imatinib complex (green) with src
(C-helix-out conformation) (gray) (PDB ID: 2SRC).[13] Side
chains of key residues are shown as sticks. Hydrogen bond
between lck residues W238/E237 and src residues W260/Q312 are
shown as dotted line. Also shown are side chains of src A259 and
lck N290. These residues are at the same position as lck residue
E237 and src residue Q312, respectively.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2008,
70,
1451-1460)
copyright 2008.
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