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Crystal structures of antibiotic-bound complexes of aminoglycoside 2''-phosphotransferase IVa highlight the diversity in substrate binding modes among aminoglycoside kinases.

Shi K, Houston DR, Berghuis AM
Biochemistry 50 6237-44 (2011)
Related entries: 3sg8, 3sg9

Cited: 14 times
EuropePMC logo PMID: 21678960

Abstract

Aminoglycoside 2''-phosphotransferase IVa [APH(2'')-IVa] is a member of a family of bacterial enzymes responsible for medically relevant resistance to antibiotics. APH(2'')-IVa confers high-level resistance against several clinically used aminoglycoside antibiotics in various pathogenic Enterococcus species by phosphorylating the drug, thereby preventing it from binding to its ribosomal target and producing a bactericidal effect. We describe here three crystal structures of APH(2'')-IVa, one in its apo form and two in complex with a bound antibiotic, tobramycin and kanamycin A. The apo structure was refined to a resolution of 2.05 Å, and the APH(2'')-IVa structures with tobramycin and kanamycin A bound were refined to resolutions of 1.80 and 2.15 Å, respectively. Comparison among the structures provides insight concerning the substrate selectivity of this enzyme. In particular, conformational changes upon substrate binding, involving rotational shifts of two distinct segments of the enzyme, are observed. These substrate-induced shifts may also rationalize the altered substrate preference of APH(2'')-IVa in comparison to those of other members of the APH(2'') subfamily, which are structurally closely related. Finally, analysis of the interactions between the enzyme and aminoglycoside reveals a distinct binding mode as compared to the intended ribosomal target. The differences in the pattern of interactions can be utilized as a structural basis for the development of improved aminoglycosides that are not susceptible to these resistance factors.

Reviews - 3sgc mentioned but not cited (1)

  1. Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections. Labby KJ, Garneau-Tsodikova S. Future Med Chem 5 1285-1309 (2013)


Reviews citing this publication (4)

  1. Resilience of biochemical activity in protein domains in the face of structural divergence. Zhang D, Iyer LM, Burroughs AM, Aravind L. Curr Opin Struct Biol 26 92-103 (2014)
  2. Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance. Shi K, Caldwell SJ, Fong DH, Berghuis AM. Front Cell Infect Microbiol 3 22 (2013)
  3. Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities. Thamban Chandrika N, Garneau-Tsodikova S. Chem Soc Rev 47 1189-1249 (2018)
  4. Design principles underpinning the regulatory diversity of protein kinases. Oruganty K, Kannan N. Philos Trans R Soc Lond B Biol Sci 367 2529-2539 (2012)

Articles citing this publication (9)

  1. Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes. Cox G, Ejim L, Stogios PJ, Koteva K, Bordeleau E, Evdokimova E, Sieron AO, Savchenko A, Serio AW, Krause KM, Wright GD. ACS Infect Dis 4 980-987 (2018)
  2. Chemical and structural insights into the regioversatility of the aminoglycoside acetyltransferase Eis. Houghton JL, Biswas T, Chen W, Tsodikov OV, Garneau-Tsodikova S. Chembiochem 14 2127-2135 (2013)
  3. Structural basis for dual nucleotide selectivity of aminoglycoside 2''-phosphotransferase IVa provides insight on determinants of nucleotide specificity of aminoglycoside kinases. Shi K, Berghuis AM. J Biol Chem 287 13094-13102 (2012)
  4. Aminoglycoside 2''-phosphotransferase IIIa (APH(2'')-IIIa) prefers GTP over ATP: structural templates for nucleotide recognition in the bacterial aminoglycoside-2'' kinases. Smith CA, Toth M, Frase H, Byrnes LJ, Vakulenko SB. J Biol Chem 287 12893-12903 (2012)
  5. Tobramycin Variants with Enhanced Ribosome-Targeting Activity. Fosso MY, Zhu H, Green KD, Garneau-Tsodikova S, Fredrick K. Chembiochem 16 1565-1570 (2015)
  6. Structural and kinetic characterization of (S)-1-amino-2-propanol kinase from the aminoacetone utilization microcompartment of Mycobacterium smegmatis. Mallette E, Kimber MS. J Biol Chem 293 19909-19918 (2018)
  7. Antibiotic Binding Drives Catalytic Activation of Aminoglycoside Kinase APH(2″)-Ia. Caldwell SJ, Huang Y, Berghuis AM. Structure 24 935-945 (2016)
  8. Aminoglycoside binding and catalysis specificity of aminoglycoside 2″-phosphotransferase IVa: A thermodynamic, structural and kinetic study. Kaplan E, Guichou JF, Chaloin L, Kunzelmann S, Leban N, Serpersu EH, Lionne C. Biochim Biophys Acta 1860 802-813 (2016)
  9. Structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2''-phosphotransferases. Smith CA, Toth M, Stewart NK, Maltz L, Vakulenko SB. Acta Crystallogr D Struct Biol 75 1129-1137 (2019)


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