Although partially or totally devoid of any ATP binding or hydrolysis, pseudokinases are now recognized as key players in cell signaling. However, their functioning is still unclear for a number of such pseudokinases encoded in the mammalian genomes. Here we describe the crystal structure of the folded region of SGK223, a large pseudokinase from rat. We could solve the crystal structure by molecular replacement, at a 3.0 A resolution, despite a low overall sequence identity (20-25% over the whole kinase domain), using the software Phenix, an ensemble of partial models built using our server @TOME-2 and data recorded automatically on the beamline MASSIF-1 at the ESRF synchrotron.

The structure contains a classical protein kinase fold, devoid of any ATP-binding activity. It also highlighted several sequence motifs conserved in other psudokinases and extend the corresponding superfamily. Interestingly, these pseudokinases possess N- and C-terminal extensions forming an original dimerization domain. This dimeric pseudokinases have been linked to cancer by up-regulating protein tyrosine phosphorylation. Our results suggest a structural model for understanding how pseudokinases induce protein tyrosine phosphorylation [1,2].