3WZD

KDR in complex with ligand lenvatinib

Summary for 3WZD

• Entry DOI: 10.2210/pdb3wzd/pdb
• Related: 3WZE
• Descriptor: Vascular endothelial growth factor receptor 2, 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxamide, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (7 entities in total)
• Functional Keywords: kdr receptor kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968
• Total number of polymer chains: 1
• Total formula weight: 36821.08

Authors

Okamoto, K.,Ikemori_Kawada, M.,Inoue, A.,Matsui, J. (deposition date: 2014-09-24, release date: 2015-05-27, Last modification date: 2024-11-20)

Primary citation

Okamoto, K.,Ikemori-Kawada, M.,Jestel, A.,von Konig, K.,Funahashi, Y.,Matsushima, T.,Tsuruoka, A.,Inoue, A.,Matsui, J.
Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.
ACS MED.CHEM.LETT., 6:89-94, 2015

PubMed Abstract: 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.

PubMed: 25589937
DOI: 10.1021/ml500394m

Experimental method

X-RAY DIFFRACTION (1.57 Å)