2XYU

Crystal structure of EphA4 kinase domain in complex with VUF 12058

Summary for 2XYU

• Entry DOI: 10.2210/pdb2xyu/pdb
• Related: 1B0X
• Descriptor: EPHRIN TYPE-A RECEPTOR 4,, GLYCEROL, 5-(5-FLUORO-2-METHYLPHENYL)-6,7,8,9-TETRAHYDRO-3H-PYRAZOLO[3,4-C]ISOQUINOLIN-1-AMINE, ... (4 entities in total)
• Functional Keywords: signaling protein, transferase
• Biological source: MUS MUSCULUS (MOUSE)
• Cellular location: Cell membrane; Single-pass type I membrane protein: Q03137
• Total number of polymer chains: 1
• Total formula weight: 33081.23

Authors

Farenc, C.J.A.,Celie, P.H.N.,vanLinden, O.P.J.,Siegal, G. (deposition date: 2010-11-19, release date: 2011-11-30, Last modification date: 2023-12-20)

Primary citation

Van Linden, O.P.,Farenc, C.J.A.,Zoutman, W.H.,Hameetman, L.,Wijtmans, M.,Leurs, R.,Tensen, C.P.,Siegal, G.,De Esch, I.J.
Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase.
Eur.J.Med.Chem., 47:493-, 2012

PubMed Abstract: The in silico identification, optimization and crystallographic characterization of a 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine scaffold as an inhibitor for the EPHA4 receptor tyrosine kinase is described. A database containing commercially available compounds was subjected to an in silico screening procedure which was focused on finding novel, EPHA4 hinge binding fragments. This resulted in the identification of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine derivatives as EPHA4 inhibitors. Hit exploration yielded a compound with 2 μM (IC(50)) affinity for the EPHA4 receptor tyrosine kinase domain. Soaking experiments into a crystal of the EPHA4 kinase domain gave a 2.11Å X-ray structure of the EPHA4 - inhibitor complex, which confirmed the binding mode of the scaffold as proposed by the initial in silico work. The results underscore the strength of fragment based in silico screening as a tool for the discovery of novel lead compounds as small molecule kinase inhibitors.

PubMed: 22137457
DOI: 10.1016/J.EJMECH.2011.11.020

Experimental method

X-RAY DIFFRACTION (2.117 Å)