Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1

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  • Yonca Ural-Blimke, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Ali Flayhan, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Jan Strauss, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Vasileios Rantos, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Kim Bartels, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Rolf Nielsen, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Els Pardon, Vrije Universiteit Brussel
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  • Jan Steyaert, Vrije Universiteit Brussel
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  • Jan Kosinski, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
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  • Esben M Quistgaard
  • Christian Löw, Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Hamburg, Germany., Karolinska Institutet

Members of the solute carrier 15 family (SLC15) transport di- and tripeptides as well as peptidomimetic drugs across the cell membrane. Structures of bacterial homologues have provided valuable information on the binding and transport of their natural substrates, but many do not transport medically relevant drugs. In contrast, a homologue from Escherichia coli, DtpA (dipeptide and tripeptide permease), shows a high similarity to human PepT1 (SLC15A1) in terms of ligand selectivity and transports a similar set of drugs. Here, we present the crystal structure of DtpA in ligand-free form (at 3.30 angstrom resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 angstrom resolution) supported by biochemical data. We show that valganciclovir unexpectedly binds with the ganciclovir moiety mimicking the N-terminal residue of a canonical peptide substrate. On the basis of a homology model we argue that this binding mode also applies to the human PepT1 transporter. Our results provide new insights into the binding mode of prodrugs and will assist the rational design of drugs with improved absorption rates.

OriginalsprogEngelsk
TidsskriftJournal of the American Chemical Society
Vol/bind141
Nummer6
Sider (fra-til)2404-2412
Antal sider9
ISSN0002-7863
DOI
StatusUdgivet - feb. 2019

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