ArticleThe Journal of biological chemistry2012
Aminoglycoside 2''-phosphotransferase IIIa (APH(2'')-IIIa) prefers GTP over ATP: structural templates for nucleotide recognition in the bacterial aminoglycoside-2'' 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 13 papers.
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13 citing papers in PubMed, 26 citations in OpenAlex.
- Structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2''-phosphotransferases.Acta crystallographica. Section D, Structural biology · 2019Article
- Crystal structure of the TreS:Pep2 complex, initiating α-glucan synthesis in the GlgE pathway of mycobacteria.The Journal of biological chemistry · 2019Article
- Nucleoside triphosphate cosubstrates control the substrate profile and efficiency of aminoglycoside 3'-MedChemComm · 2018Article
- Identification and classification of small molecule kinases: insights into substrate recognition and specificity.BMC evolutionary biology · 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
- 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
- Bulky "gatekeeper" residue changes the cosubstrate specificity of aminoglycoside 2''-phosphotransferase IIa.Antimicrobial agents and chemotherapy · 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
- Novel aminoglycoside 2''-phosphotransferase identified in a gram-negative pathogen.Antimicrobial agents and chemotherapy · 2013Article
- Revisiting the nucleotide and aminoglycoside substrate specificity of the bifunctional aminoglycoside acetyltransferase(6')-Ie/aminoglycoside phosphotransferase(2'')-Ia enzyme.The Journal of biological chemistry · 2012Article
- Mechanistic characterization of the 5'-triphosphate-dependent activation of PKR: lack of 5'-end nucleobase specificity, evidence for a distinct triphosphate binding site, and a critical role for the dsRBD.RNA (New York, N.Y.) · 2012Article
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5 authors at 2 institutions in 1 country.
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Abstract
Contrary to the accepted dogma that ATP is the canonical phosphate donor in aminoglycoside kinases and protein kinases, it was recently demonstrated that all members of the bacterial aminoglycoside 2''-phosphotransferase IIIa (APH(2'')) aminoglycoside kinase family are unique in their ability to utilize GTP as a cofactor for antibiotic modification. Here we describe the structural determinants for GTP recognition in these enzymes. The crystal structure of the GTP-dependent APH(2'')-IIIa shows that although this enzyme has templates for both ATP and GTP binding superimposed on a single nucleotide specificity motif, access to the ATP-binding template is blocked by a bulky tyrosine residue. Substitution of this tyrosine by a smaller amino acid opens access to the ATP template. Similar GTP binding templates are conserved in other bacterial aminoglycoside kinases, whereas in the structurally related eukaryotic protein kinases this template is less conserved. The aminoglycoside kinases are important antibiotic resistance enzymes in bacteria, whose wide dissemination severely limits available therapeutic options, and the GTP binding templates could be exploited as new, previously unexplored targets for inhibitors of these clinically important enzymes.
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