Structural studies of aminoglycoside antibiotic-RNA aptamer complexes by nuclear magnetic resonance spectroscopic techniques in aqueous solution

Aminoglycoside antibiotics can target ribosomal, retroviral and catalytic RNAs, thus inhibiting protein synthesis, viral replication and ribozyme activity, respectively. In order to understand the molecular basis of aminoglycoside antibiotic-RNA interaction, we determined three-dimensional solution structures of several aminoglycoside-RNA aptamer complexes, using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) calculations. We solved structures of tobramycin-binding RNA aptamers I and II in complex with tobramycin, and neomycin B-binding RNA aptamer in complex with neomycin B. Although the RNA aptamers that bind to tobramycin and neomycin B were identified in different laboratories using different in vitro selection protocols, the tobramycin- and neomycin B-RNA aptamer complexes utilize common principles for generating RNA-binding pockets for the aminoglycoside antibiotics. In each case, the 2-deoxystreptamine ring I and an attached pyranose ring are encapsulated within the major groove binding pocket lined by mismatch pairs which is capped over by a looped-out base. The antibiotics are anchored in place through intermolecular hydrogen bonds involving charged amine groups of the antibiotics with acceptor atoms on the base pair edges and the backbone phosphates. These structures are helpful in understanding the molecular basis of RNA-small molecule recognition, and can be helpful in the design of small organic molecules that target RNA for therapeutic purpose.