Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1
| Autor: | Yonca Ural-Blimke, Jan Kosinski, Els Pardon, Esben M. Quistgaard, Jan Strauss, Vasileios Rantos, Ali Flayhan, Jan Steyaert, Kim Bartels, Christian Löw, Rolf Nielsen |
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| Přispěvatelé: | Department of Bio-engineering Sciences, Structural Biology Brussels |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular MECHANISM Chemistry(all) Peptidomimetic Stereochemistry Protein Conformation PREDICTION Tripeptide Plasma protein binding 010402 general chemistry 01 natural sciences Biochemistry Peptide Transporter 1 Catalysis chemistry.chemical_compound Colloid and Surface Chemistry DOMAIN Humans Valganciclovir TOOL POT FAMILY Dipeptide MUTAGENESIS Permease Chemistry Escherichia coli Proteins HPEPT1 Rational design Membrane Transport Proteins General Chemistry Prodrug Ligand (biochemistry) 0104 chemical sciences 3. Good health MODEL BEAMLINE ddc:540 Protein Binding |
| Zdroj: | Journal of the American Chemical Society, 141 (6). pp. 2404-2412. Ural-Blimke, Y, Flayhan, A, Strauss, J, Rantos, V, Bartels, K, Nielsen, R, Pardon, E, Steyaert, J, Kosinski, J, Quistgaard, E M & Löw, C 2019, ' Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1 ', Journal of the American Chemical Society, vol. 141, no. 6, pp. 2404-2412 . https://doi.org/10.1021/jacs.8b11343 'Journal of the American Chemical Society ', vol: 141, pages: 2404-2412 (2019) Journal of the American Chemical Society 141(6), 2404-2412 (2019). doi:10.1021/jacs.8b11343 Journal of the American Chemical Society |
| ISSN: | 0002-7863 |
| DOI: | 10.1021/jacs.8b11343 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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