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PDBsum entry 3wzd
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Transferase/transferase inhibitor
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PDB id
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3wzd
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References listed in PDB file
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Key reference
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Title
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Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.
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Authors
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K.Okamoto,
M.Ikemori-Kawada,
A.Jestel,
K.Von könig,
Y.Funahashi,
T.Matsushima,
A.Tsuruoka,
A.Inoue,
J.Matsui.
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Ref.
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Acs Med Chem Lett, 2015,
6,
89-94.
[DOI no: ]
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PubMed id
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Abstract
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Lenvatinib is an oral multikinase inhibitor that selectively inhibits vascular
endothelial growth factor (VEGF) receptors 1 to 3 and other proangiogenic and
oncogenic pathway-related receptor tyrosine kinases. To elucidate the origin of
the potency of lenvatinib in VEGF receptor 2 (VEGFR2) inhibition, we conducted a
kinetic interaction analysis of lenvatinib with VEGFR2 and X-ray analysis of the
crystal structure of VEGFR2-lenvatinib complexes. Kinetic analysis revealed that
lenvatinib had a rapid association rate constant and a relatively slow
dissociation rate constant in complex with VEGFR2. Co-crystal structure analysis
demonstrated that lenvatinib binds at its ATP mimetic quinoline moiety to the
ATP binding site and to the neighboring region via a cyclopropane ring, adopting
an Asp-Phe-Gly (DFG)-"in" conformation. These results suggest that
lenvatinib is very distinct in its binding mode of interaction compared to the
several approved VEGFR2 kinase inhibitors.
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