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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Kdr in complex with ligand lenvatinib
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Structure:
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Vascular endothelial growth factor receptor 2. Chain: a. Fragment: kinase domain (unp residues 814-940, 991-1172). Synonym: vegfr-2, fetal liver kinase 1, flk-1, kinase insert domain receptor, kdr, protein-tyrosine kinase receptor flk-1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1, vegfr2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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1.57Å
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R-factor:
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0.184
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R-free:
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0.212
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Authors:
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K.Okamoto,M.Ikemori_kawada,A.Inoue,J.Matsui
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Key ref:
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K.Okamoto
et al.
(2015).
Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.
Acs Med Chem Lett,
6,
89-94.
PubMed id:
DOI:
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Date:
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24-Sep-14
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Release date:
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27-May-15
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PROCHECK
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Headers
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References
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P35968
(VGFR2_HUMAN) -
Vascular endothelial growth factor receptor 2 from Homo sapiens
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Seq:
Struc:
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1356 a.a.
278 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Acs Med Chem Lett
6:89-94
(2015)
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PubMed id:
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Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.
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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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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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