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

Elife. 2014 Jul 31:3: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 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.

Keywords: Vibrio cholerae; anticancer drugs; antiviral drugs; drug delivery; membrane transport; nucleoside.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Biological Transport
  • Crystallography, X-Ray
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / chemistry
  • Deoxycytidine / metabolism
  • Female
  • Gemcitabine
  • Gene Expression
  • Humans
  • Kinetics
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Molecular Docking Simulation
  • Nucleoside Transport Proteins / chemistry*
  • Nucleoside Transport Proteins / genetics
  • Nucleoside Transport Proteins / metabolism
  • Oocytes / cytology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribavirin / chemistry
  • Ribavirin / metabolism
  • Substrate Specificity
  • Thermodynamics
  • Uridine / chemistry
  • Uridine / metabolism*
  • Vibrio cholerae / chemistry
  • Vibrio cholerae / metabolism
  • Xenopus laevis

Substances

  • Bacterial Proteins
  • Membrane Transport Proteins
  • Nucleoside Transport Proteins
  • Recombinant Proteins
  • cif nucleoside transporter
  • Deoxycytidine
  • Ribavirin
  • Uridine
  • Gemcitabine