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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 Biol

Publication Date





40s, RIO kinase, RIOK2, crystal structure, inhibitor, ribosome assembly, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Humans, Molecular Structure, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Structure-Activity Relationship