ArticleThe Journal of biological chemistry2012
Structural basis for dual nucleotide selectivity of aminoglycoside 2''-phosphotransferase IVa provides insight on determinants of nucleotide specificity of aminoglycoside kinases.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- APH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.ChemMedChem · 2025Article
- Resistance to last-resort antibiotics in enterococci.FEMS microbiology reviews · 2025Review
- Discovery and characterization of genes conferring natural resistance to the antituberculosis antibiotic capreomycin.Communications biology · 2023Article
- Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation.RSC medicinal chemistry · 2023Review
- Structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2''-phosphotransferases.Acta crystallographica. Section D, Structural biology · 2019Article
- Antibiotic resistance and inhibition mechanism of novel aminoglycoside phosphotransferase APH(5) from B. subtilis subsp. subtilis strain RK.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2019Article
- Role of protein kinase CK2 in antitumor drug resistance.Journal of experimental & clinical cancer research : CR · 2019Review
- Nucleoside triphosphate cosubstrates control the substrate profile and efficiency of aminoglycoside 3'-MedChemComm · 2018Article
- Look and Outlook on Enzyme-Mediated Macrolide Resistance.Frontiers in microbiology · 2018Review
- Aminoglycoside binding and catalysis specificity of aminoglycoside 2″-phosphotransferase IVa: A thermodynamic, structural and kinetic study.Biochimica et biophysica acta · 2016Article
- The Biosynthesis of Capuramycin-type Antibiotics: IDENTIFICATION OF THE A-102395 BIOSYNTHETIC GENE CLUSTER, MECHANISM OF SELF-RESISTANCE, AND FORMATION OF URIDINE-5'-CARBOXAMIDE.The Journal of biological chemistry · 2015Article
- Structure of mycobacterial maltokinase, the missing link in the essential GlgE-pathway.Scientific reports · 2015Article
- New trends in aminoglycosides use.MedChemComm · 2014Article
- Structure of the phosphotransferase domain of the bifunctional aminoglycoside-resistance enzyme AAC(6')-Ie-APH(2'')-Ia.Acta crystallographica. Section D, Biological crystallography · 2014Article
- Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance.The Biochemical journal · 2013Article
- Bulky "gatekeeper" residue changes the cosubstrate specificity of aminoglycoside 2''-phosphotransferase IIa.Antimicrobial agents and chemotherapy · 2013Article
- Induction and translocation of tissue transglutaminase isoforms increased phosphorylation in retinoic acid treated erythroleukemia cells.The protein journal · 2013Article
- Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections.Future medicinal chemistry · 2013Review
- Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.Frontiers in cellular and infection microbiology · 2013Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Enzymatic phosphorylation through a family of enzymes called aminoglycoside O-phosphotransferases (APHs) is a major mechanism by which bacteria confer resistance to aminoglycoside antibiotics. Members of the APH(2″) subfamily are of particular clinical interest because of their prevalence in pathogenic strains and their broad substrate spectra. APH(2″) enzymes display differential preferences between ATP or GTP as the phosphate donor, with aminoglycoside 2″-phosphotransferase IVa (APH(2″)-IVa) being a member that utilizes both nucleotides at comparable efficiencies. We report here four crystal structures of APH(2″)-IVa, two of the wild type enzyme and two of single amino acid mutants, each in complex with either adenosine or guanosine. Together, these structures afford a detailed look at the nucleoside-binding site architecture for this enzyme and reveal key elements that confer dual nucleotide specificity, including a solvent network in the interior of the nucleoside-binding pocket and the conformation of an interdomain linker loop. Steady state kinetic studies, as well as sequence and structural comparisons with members of the APH(2″) subfamily and other aminoglycoside kinases, rationalize the different substrate preferences for these enzymes. Finally, despite poor overall sequence similarity and structural homology, analysis of the nucleoside-binding pocket of APH(2″)-IVa shows a striking resemblance to that of eukaryotic casein kinase 2 (CK2), which also exhibits dual nucleotide specificity. These results, in complement with the multitude of existing inhibitors against CK2, can serve as a structural basis for the design of nucleotide-competitive inhibitors against clinically relevant APH enzymes.
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