Analysis of the π-π stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands

David D. Boehr, Adam R. Farley, Gerard D. Wright, James R. Cox

Research output: Contribution to journalArticle

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Abstract

A key contact in the active site of an aminoglycoside phosphotransferase enzyme (APH(3′)-IIIa) is a π-π stacking interaction between Tyr42 and the adenine ring of bound nucleotides. We investigated the prevalence of similar Tyr-adenine contacts and found that many different protein systems employ Tyr residues in the recognition of the adenine ring. The geometry of these stacking interactions suggests that electrostatics play a role in the attraction between these aromatic systems. Kinetic and calorimetric experiments on wild-type and mutant forms of APH(3′)-IIIa yielded further experimental evidence of the importance of electrostatics in the adenine binding region and suggested that the stacking interaction contributes ∼2 kcal/mol of binding energy. This type of information concerning the forces that govern nucleotide binding in APH(3′)-IIIa will facilitate inhibitor design strategies that target the nucleotide binding site of APH-type enzymes.

Original languageEnglish (US)
Pages (from-to)1209-1217
Number of pages9
JournalChemistry and Biology
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2002

Fingerprint

Kanamycin Kinase
Aminoglycosides
Adenine
Phosphotransferases
Nucleotides
Anti-Bacterial Agents
Ligands
Static Electricity
Electrostatics
Enzymes
Binding energy
Catalytic Domain
Binding Sites
Kinetics
Geometry
Proteins
Experiments

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

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abstract = "A key contact in the active site of an aminoglycoside phosphotransferase enzyme (APH(3′)-IIIa) is a π-π stacking interaction between Tyr42 and the adenine ring of bound nucleotides. We investigated the prevalence of similar Tyr-adenine contacts and found that many different protein systems employ Tyr residues in the recognition of the adenine ring. The geometry of these stacking interactions suggests that electrostatics play a role in the attraction between these aromatic systems. Kinetic and calorimetric experiments on wild-type and mutant forms of APH(3′)-IIIa yielded further experimental evidence of the importance of electrostatics in the adenine binding region and suggested that the stacking interaction contributes ∼2 kcal/mol of binding energy. This type of information concerning the forces that govern nucleotide binding in APH(3′)-IIIa will facilitate inhibitor design strategies that target the nucleotide binding site of APH-type enzymes.",
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Analysis of the π-π stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands. / Boehr, David D.; Farley, Adam R.; Wright, Gerard D.; Cox, James R.

In: Chemistry and Biology, Vol. 9, No. 11, 01.11.2002, p. 1209-1217.

Research output: Contribution to journalArticle

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AU - Boehr, David D.

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AU - Wright, Gerard D.

AU - Cox, James R.

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AB - A key contact in the active site of an aminoglycoside phosphotransferase enzyme (APH(3′)-IIIa) is a π-π stacking interaction between Tyr42 and the adenine ring of bound nucleotides. We investigated the prevalence of similar Tyr-adenine contacts and found that many different protein systems employ Tyr residues in the recognition of the adenine ring. The geometry of these stacking interactions suggests that electrostatics play a role in the attraction between these aromatic systems. Kinetic and calorimetric experiments on wild-type and mutant forms of APH(3′)-IIIa yielded further experimental evidence of the importance of electrostatics in the adenine binding region and suggested that the stacking interaction contributes ∼2 kcal/mol of binding energy. This type of information concerning the forces that govern nucleotide binding in APH(3′)-IIIa will facilitate inhibitor design strategies that target the nucleotide binding site of APH-type enzymes.

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