Abstract
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.
Highlights
Nucleosides play critical roles in biology as precursors to nucleic acids and the energy currency of the cell and serve as signaling molecules (King et al, 2006; Rose and Coe, 2008; Molina-Arcas et al, 2009)
concentrative nucleoside transporters (CNTs) utilize the energy of ion gradients to actively transport nucleosides into the cell against their concentration gradients while equilibrative nucleoside transporters (ENTs) transport nucleosides down their chemical gradients without the requirement of any additional energy source (Gray et al, 2004b)
The nucleoside-binding site of vcCNT-7C8C and equilibrium-binding measurements vcCNT forms a homotrimer with each protomer possessing its own nucleoside-binding site and permeation pathway (Figure 1A)
Summary
Nucleosides play critical roles in biology as precursors to nucleic acids and the energy currency of the cell and serve as signaling molecules (King et al, 2006; Rose and Coe, 2008; Molina-Arcas et al, 2009). Nucleoside analogs have clinical applications as anticancer and antiviral drugs (Damaraju et al, 2003; Jordheim and Dumontet, 2007). Because of their immense biological and clinical importance, efficient entry of nucleosides and their analogs into the cell is crucial to human health and disease. There are two types of NTs in humans: concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). CNTs utilize the energy of ion gradients to actively transport nucleosides into the cell against their concentration gradients while ENTs transport nucleosides down their chemical gradients without the requirement of any additional energy source (Gray et al, 2004b)
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