4GK3

Human EphA3 Kinase domain in complex with ligand 87

4GK3 の概要

• エントリーDOI: 10.2210/pdb4gk3/pdb
• 関連するPDBエントリー: 4GK2 4GK4
• 分子名称: EPH receptor A3, 8-butyl-1-methyl-7-(2-methylphenyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase, atp-binding, phosphorylation, membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40809.58

構造登録者

Dong, J.,Caflisch, A. (登録日: 2012-08-10, 公開日: 2013-01-23, 最終更新日: 2023-11-08)

主引用文献

Lafleur, K.,Dong, J.,Huang, D.,Caflisch, A.,Nevado, C.
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, 2013

PubMed 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.

PubMed: 23253074
DOI: 10.1021/jm301187e

実験手法

X-RAY DIFFRACTION (1.898 Å)