6FNG

Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with an isomer of NVP-BHG712

6FNG の概要

• エントリーDOI: 10.2210/pdb6fng/pdb
• 分子名称: Ephrin type-A receptor 2, 4-methyl-3-[(2-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-~{N}-[3-(trifluoromethyl)phenyl]benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, protein tyrosine kinase, transferase
• 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: 35338.73

構造登録者

Kudlinzki, D.,Troester, A.,Witt, K.,Linhard, V.L.,Gande, S.L.,Saxena, K.,Schwalbe, H. (登録日: 2018-02-04, 公開日: 2018-08-08, 最終更新日: 2024-01-17)

主引用文献

Troster, A.,Heinzlmeir, S.,Berger, B.T.,Gande, S.L.,Saxena, K.,Sreeramulu, S.,Linhard, V.,Nasiri, A.H.,Bolte, M.,Muller, S.,Kuster, B.,Medard, G.,Kudlinzki, D.,Schwalbe, H.
NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family.
ChemMedChem, 13:1629-1633, 2018

PubMed Abstract: Erythropoietin-producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

PubMed: 29928781
DOI: 10.1002/cmdc.201800398

実験手法

X-RAY DIFFRACTION (1.038 Å)