Date:december 13, 2013

39. Structure of the Toxoplasma gondii ROP18 Kinase Domain Reveals a Second Ligand Binding Pocket Required for Acute Virulence.

39 Structure of the Toxoplasma gondii ROP18Lim D, Gold DA, Julien L, Rosowski EE*, Niedelman W*, Yaffe MB#, Saeij JP#. The Journal of Biological Chemistry. 288(48):34968-80; 2013. PDF

To further our understanding of ROP18 regulation and function, we have solved the crystal structure of its kinase domain and identified features important for virulence in mice. Our structure is the first determined for a catalytically active rhoptry kinase and builds on data from previously published crystal structures of the pseudokinase domains of ROP2 (PDB accession codes 2W1Z and 3DZO), ROP8 (PDB code 3BYV), and ROP5 (PDB code 3Q60). Unlike ROP18, all three of these ROPK proteins do not function by phosphorylating downstream targets. Our structure of the ROP18 kinase domain disproves a previously proposed autoinhibitory mechanism. Importantly, the structure also identifies a novel second ligand binding pocket adjacent to the active site, which is critical for ROP18-mediated virulence and may provide an additional substrate specificity determinant or allosteric regulatory site.