Abstract
BackgroundMany prokaryotic kinases that phosphorylate small molecule substrates, such as antibiotics, lipids and sugars, are evolutionarily related to Eukaryotic Protein Kinases (EPKs). These Eukaryotic-Like Kinases (ELKs) share the same overall structural fold as EPKs, but differ in their modes of regulation, substrate recognition and specificity—the sequence and structural determinants of which are poorly understood.ResultsTo better understand the basis for ELK specificity, we applied a Bayesian classification procedure designed to identify sequence determinants responsible for functional divergence. This reveals that a large and diverse family of aminoglycoside kinases, characterized members of which are involved in antibiotic resistance, fall into major sub-groups based on differences in putative substrate recognition motifs. Aminoglycoside kinase substrate specificity follows simple rules of alternating hydroxyl and amino groups that is strongly correlated with variations at the DFG + 1 position.ConclusionsSubstrate specificity determining features in small molecule kinases are mostly confined to the catalytic core and can be identified based on quantitative sequence and crystal structure comparisons.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0576-x) contains supplementary material, which is available to authorized users.
Highlights
Many prokaryotic kinases that phosphorylate small molecule substrates, such as antibiotics, lipids and sugars, are evolutionarily related to Eukaryotic Protein Kinases (EPKs)
EPK-like kinases (ELK) are evolutionarily related to Eukaryotic Protein Kinases (EPKs) that regulate diverse cellular processes through the controlled phosphorylation of serine, threonine and tyrosine residues on protein substrates [3,4,5,6,7]
A core domain commonly shared by EPKs and ELKs was defined based on available sequences and crystal structures
Summary
To better understand the basis for ELK specificity, we applied a Bayesian classification procedure designed to identify sequence determinants responsible for functional divergence. This reveals that a large and diverse family of aminoglycoside kinases, characterized members of which are involved in antibiotic resistance, fall into major sub-groups based on differences in putative substrate recognition motifs. Aminoglycoside kinase substrate specificity follows simple rules of alternating hydroxyl and amino groups that is strongly correlated with variations at the DFG + 1 position
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