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.
Copyright © 2014, Johnson et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / chemistry*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Binding Sites
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Biological Transport
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Crystallography, X-Ray
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / chemistry
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Deoxycytidine / metabolism
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Female
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Gemcitabine
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Gene Expression
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Humans
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Kinetics
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Membrane Transport Proteins / chemistry*
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Molecular Docking Simulation
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Nucleoside Transport Proteins / chemistry*
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Nucleoside Transport Proteins / genetics
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Nucleoside Transport Proteins / metabolism
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Oocytes / cytology
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Oocytes / drug effects
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Oocytes / metabolism
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Protein Binding
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Quantitative Structure-Activity Relationship
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ribavirin / chemistry
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Ribavirin / metabolism
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Substrate Specificity
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Thermodynamics
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Uridine / chemistry
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Uridine / metabolism*
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Vibrio cholerae / chemistry
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Vibrio cholerae / metabolism
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Xenopus laevis
Substances
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Bacterial Proteins
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Membrane Transport Proteins
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Nucleoside Transport Proteins
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Recombinant Proteins
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cif nucleoside transporter
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Deoxycytidine
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Ribavirin
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Uridine
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Gemcitabine