PDBsum entry 4gk3

Transferase/transferase inhibitor

PDB id: 4gk3

Contents

Protein chain

275 a.a.

Ligands

L87

Waters ×218

PDB id:

4gk3

Name:

Transferase/transferase inhibitor

Title:

Human epha3 kinase domain in complex with ligand 87

Structure:

Eph receptor a3. Chain: a. Fragment: kinase domain, unp residues 606-947. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: epha3. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.180 R-free: 0.213

Authors:

J.Dong,A.Caflisch

Key ref:

K.Lafleur et al. (2013). Optimization of inhibitors of the tyrosine kinase EphB4. 2. Cellular potency improvement and binding mode validation by X-ray crystallography. J Med Chem, 56, 84-96. PubMed id: 23253074

Date:

10-Aug-12 Release date: 23-Jan-13

Protein chain

P29320  (EPHA3_HUMAN) -  Ephrin type-A receptor 3 from Homo sapiens

Seq: 983 a.a.

Struc: 275 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 56:84-96 (2013)

PubMed id: 23253074

Optimization of inhibitors of the tyrosine kinase EphB4. 2. Cellular potency improvement and binding mode validation by X-ray crystallography.

K.Lafleur, J.Dong, D.Huang, A.Caflisch, C.Nevado.

ABSTRACT

Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.