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The RIO kinases (RIOKs) are a universal family of atypical kinases that are essential for assembly of the pre-40S ribosome complex. Here, we present the crystal structure of human RIO kinase 2 (RIOK2) bound to a specific inhibitor. This first crystal structure of an inhibitor-bound RIO kinase reveals the binding mode of the inhibitor and explains the structure-activity relationship of the inhibitor series. The inhibitor binds in the ATP-binding site and forms extensive hydrophobic interactions with residues at the entrance to the ATP-binding site. Analysis of the conservation of active site residues reveals the reasons for the specificity of the inhibitor for RIOK2 over RIOK1 and RIOK3, and it provides a template for inhibitor design against the human RIOK family.

Original publication




Journal article


Open biology

Publication Date





1 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ , UK.


Humans, Protein-Serine-Threonine Kinases, Protein Kinase Inhibitors, Crystallography, X-Ray, Binding Sites, Molecular Structure, Catalytic Domain, Protein Conformation, Protein Binding, Structure-Activity Relationship