3WZD

KDR in complex with ligand lenvatinib

PDB DOI: https://doi.org/10.2210/pdb3WZD/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): Yes

Deposited: 2014-09-24 Released: 2015-05-27
Deposition Author(s): Okamoto, K., Ikemori_Kawada, M., Inoue, A., Matsui, J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.57 Å
R-Value Free: 0.212
R-Value Work: 0.181
R-Value Observed: 0.184

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.

Okamoto, K., Ikemori-Kawada, M., Jestel, A., von Konig, K., Funahashi, Y., Matsushima, T., Tsuruoka, A., Inoue, A., Matsui, J.

(2015) ACS Med Chem Lett 6: 89-94

PubMed: 25589937 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/ml500394m
Primary Citation of Related Structures:
3WZD, 3WZE

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.

Organizational Affiliation

Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.

Macromolecule Content

Total Structure Weight: 36.82 kDa
Atom Count: 2,554
Modelled Residue Count: 278
Deposited Residue Count: 309
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Vascular endothelial growth factor receptor 2	A	309	Homo sapiens	Mutation(s): 1 Gene Names: KDR, FLK1, VEGFR2 EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P35968 (Homo sapiens) Explore P35968 Go to UniProtKB: P35968
PHAROS: P35968 GTEx: ENSG00000128052
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P35968
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
LEV Query on LEV Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxamide C₂₁ H₁₉ Cl N₄ O₄ WOSKHXYHFSIKNG-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
DTT Query on DTT Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	C [auth A], D [auth A], E [auth A], F [auth A]	2,3-DIHYDROXY-1,4-DITHIOBUTANE C₄ H₁₀ O₂ S₂ VHJLVAABSRFDPM-IMJSIDKUSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A]	G [auth A], H [auth A], I [auth A], J [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A]