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Closed Access item The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition

Authors:Corzana, Francisco
Cuesta, Igor
Freire, Felix
Torrado, Mario
Bastida, Agatha
Jiménez-Barbero, Jesús
Luis Asensio, Juan
Issue Date:2007
Publisher:American Chemical Society
Citation:Journal of the American Chemical Society 129 : 2849-2865 (2007)
Abstract:Aminoglycosides are clinically relevant antibiotics that participate in a large variety of molecular recognition processes involving different RNA and protein receptors. The 3-D structures of these policationic oligosaccharides play a key role in RNA binding and therefore determine their biological activity. Herein, we show that the particular NH2/NH3 +/OH distribution within the antibiotic scaffold modulates the oligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkages have a significant influence on the antibiotic structure. A careful NMR/theoretical analysis of different natural aminoglycosides, their fragments, and synthetic derivatives proves that both hydrogen bonding and chargecharge repulsive interactions are at the origin of this effect. Current strategies to obtain new aminoglycoside derivatives are mainly focused on the optimization of the direct ligand/receptor contacts. Our results strongly suggest that the particular location of the NH2/NH3 +/OH groups within the antibiotics can also modulate their RNA binding properties by affecting the conformational preferences and inherent flexibility of these drugs. This fact should also be carefully considered in the design of new antibiotics with improved activity
Publisher version (URL):http://dx.doi.org/10.1021/ja066348x
URI:http://hdl.handle.net/10261/61141
ISSN:0002-7863
E-ISSNmetadata.dc.identifier.doi = DOI:15205126
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