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Chem Biol. 2002 Nov;9(11):1209-17.

Analysis of the pi-pi stacking interactions between the aminoglycoside antibiotic kinase APH(3')-IIIa and its nucleotide ligands.

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  • 1Antimicrobial Research Centre, Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.


A key contact in the active site of an aminoglycoside phosphotransferase enzyme (APH(3')-IIIa) is a pi-pi 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 approximately 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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