TY - JOUR TI - Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters AU - Johnson, Zachary Lee AU - Lee, Jun-Ho AU - Lee, Kiyoun AU - Lee, Minhee AU - Kwon, Do-Yeon AU - Hong, Jiyong AU - Lee, Seok-Yong A2 - Dötsch, Volker VL - 3 PY - 2014 DA - 2014/07/31 SP - e03604 C1 - eLife 2014;3:e03604 DO - 10.7554/eLife.03604 UR - https://doi.org/10.7554/eLife.03604 AB - 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. KW - membrane transport KW - anticancer drug KW - Vibrio cholerae KW - drug delivery KW - nucleoside KW - antiviral drug JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -