PDB 4E93 deposited: 2012-03-20 modified: 2012-05-09
Title Crystal structure of human Feline Sarcoma Viral Oncogene Homologue (v-FES)in complex with TAE684
Authors Choi, H.G., Deng, X., Filippakopoulos, P., Gray, N.S., Hellwig, S., Hur, W., Kanda, S., Knapp, S., Miduturu, C.V., Salah, E., Smithgall, T.E., Zhang, J., Zhou, W.
Structure factors resolution 1.84 rfactor 0.1859 rfree 0.2379
DPI 0.29 theoretical min: 0.16

The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here, we report the identification of types I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase.

Chem.Biol. 2012 Apr; 19(4):529-540 doi:10.1016/j.chembiol.2012.01.020

Cross References
Database source Identifier Description
PubMed 22520759 CBOLE2
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4E93/0 4E93 0 monomer 0 1 1 2824