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Abstract
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.
Highlights
The RIO kinases (RIOKs) are an evolutionarily conserved family of atypical kinases that are present in all eukaryotes, most archaea and some prokaryotes [1,2,3,4]
The deficiency of RIOK1 or RIO kinase 2 (RIOK2) prevents the formation of mature 40S ribosomes, and in yeast both RIOK1 and RIOK2 are essential for cytoplasmic maturation steps starting from the 20S pre-rRNA [7,8]
Since the kinase domain of RIOK2 is at the N-terminus, we constructed various different C-terminal truncations of RIOK2 in Escherichia coli expression plasmids and assessed each of them for their ability to overexpress soluble RIOK2 kinase domain
Summary
The RIO kinases (RIOKs) are an evolutionarily conserved family of atypical kinases that are present in all eukaryotes, most archaea and some prokaryotes [1,2,3,4]. The RIOKs have the protein kinase fold but lack the sequence motifs involved in substrate binding, including the activation loop Their presence in prokaryotes suggests that they are the original enzymes with the protein kinase fold, and that protein kinases capable of phosphorylating substrate proteins were a later development [1]. The deficiency of RIOK1 or RIOK2 prevents the formation of mature 40S ribosomes, and in yeast both RIOK1 and RIOK2 are essential for cytoplasmic maturation steps starting from the 20S pre-rRNA [7,8]. It appears that RIOK1 and RIOK2 have distinct roles; RIOK2 associates and dissociates from the maturing pre-40S ribosome before RIOK1 binds to a very late pre-40S ribosome [9]
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