title: Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters.
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.
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, United States.
authors.forename: Zachary Lee
authors.initials: ZL
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, United States.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University, Durham, United States.
authors.forename: Kiyoun
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University, Durham, United States.
authors.forename: Minhee
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University, Durham, United States.
authors.forename: Do-Yeon
authors.initials: DY
authors.lastname: Kwon
authors.affiliation: Department of Chemistry, Duke University, Durham, United States Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, United States sylee@biochem.duke.edu.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D018360:Crystallography, X-Ray; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D033703:Nucleoside Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012254:Ribavirin / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics; D014529:Uridine / Q000737:chemistry / Q000378:metabolism*; D014734:Vibrio cholerae / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis; D000093542:Gemcitabine
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D011994:Recombinant Proteins; C065171:cif nucleoside transporter; D003841:Deoxycytidine; D012254:Ribavirin; D014529:Uridine; D000093542:Gemcitabine
keywords: Vibrio cholerae; anticancer drugs; antiviral drugs; drug delivery; membrane transport; nucleoside
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