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 journalArticlepeer-review

70 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Analysis of the π-π stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands'. Together they form a unique fingerprint.

Cite this