1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters

  1. Zachary Lee Johnson
  2. Jun-Ho Lee
  3. Kiyoun Lee
  4. Minhee Lee
  5. Do-Yeon Kwon
  6. Jiyong Hong
  7. Seok-Yong Lee  Is a corresponding author
  1. Duke University Medical Center, United States
  2. Duke University, United States
Research Article
  • Cited 35
  • Views 2,796
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Cite this article as: eLife 2014;3:e03604 doi: 10.7554/eLife.03604

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 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.

Article and author information

Author details

  1. Zachary Lee Johnson

    Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jun-Ho Lee

    Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kiyoun Lee

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Minhee Lee

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Do-Yeon Kwon

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiyong Hong

    Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Seok-Yong Lee

    Duke University Medical Center, Durham, United States
    For correspondence
    sylee@biochem.duke.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Publication history

  1. Received: June 6, 2014
  2. Accepted: July 31, 2014
  3. Accepted Manuscript published: July 31, 2014 (version 1)
  4. Version of Record published: August 21, 2014 (version 2)

Copyright

© 2014, Johnson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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