Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters.

Publication Type:

Journal Article


Elife, Volume 3, p.e03604 (2014)


Animals, Bacterial Proteins, Binding Sites, Biological Transport, Crystallography, X-Ray, Deoxycytidine, Female, Gene Expression, Humans, Kinetics, Membrane Transport Proteins, Molecular Docking Simulation, Nucleoside Transport Proteins, Oocytes, Protein Binding, Quantitative Structure-Activity Relationship, Recombinant Proteins, Ribavirin, Substrate Specificity, Thermodynamics, Uridine, Vibrio cholerae, Xenopus laevis


<p>Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.</p>