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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Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1. / Ural-Blimke, Yonca; Flayhan, Ali; Strauss, Jan; Rantos, Vasileios; Bartels, Kim; Nielsen, Rolf; Pardon, Els; Steyaert, Jan; Kosinski, Jan; Quistgaard, Esben M; Löw, Christian.

In: Journal of the American Chemical Society, 15.01.2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Ural-Blimke, Y, Flayhan, A, Strauss, J, Rantos, V, Bartels, K, Nielsen, R, Pardon, E, Steyaert, J, Kosinski, J, Quistgaard, EM & 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. https://doi.org/10.1021/jacs.8b11343

APA

Ural-Blimke, Y., Flayhan, A., Strauss, J., Rantos, V., Bartels, K., Nielsen, R., ... 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. https://doi.org/10.1021/jacs.8b11343

CBE

Ural-Blimke Y, Flayhan A, Strauss J, Rantos V, Bartels K, Nielsen R, Pardon E, Steyaert J, Kosinski J, Quistgaard EM, 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. https://doi.org/10.1021/jacs.8b11343

MLA

Vancouver

Ural-Blimke Y, Flayhan A, Strauss J, Rantos V, Bartels K, Nielsen R et al. 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. 2019 Jan 15. https://doi.org/10.1021/jacs.8b11343

Author

Ural-Blimke, Yonca ; Flayhan, Ali ; Strauss, Jan ; Rantos, Vasileios ; Bartels, Kim ; Nielsen, Rolf ; Pardon, Els ; Steyaert, Jan ; Kosinski, Jan ; Quistgaard, Esben M ; Löw, Christian. / Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1. In: Journal of the American Chemical Society. 2019.

Bibtex

@article{0936572421ec4806b591bd9a4ab17556,
title = "Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1",
abstract = "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, 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 {\AA} resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 {\AA} 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. Based on 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.",
author = "Yonca Ural-Blimke and Ali Flayhan and Jan Strauss and Vasileios Rantos and Kim Bartels and Rolf Nielsen and Els Pardon and Jan Steyaert and Jan Kosinski and Quistgaard, {Esben M} and Christian L{\"o}w",
year = "2019",
month = "1",
day = "15",
doi = "10.1021/jacs.8b11343",
language = "English",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "ACS Publications",

}

RIS

TY - JOUR

T1 - Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1

AU - Ural-Blimke, Yonca

AU - Flayhan, Ali

AU - Strauss, Jan

AU - Rantos, Vasileios

AU - Bartels, Kim

AU - Nielsen, Rolf

AU - Pardon, Els

AU - Steyaert, Jan

AU - Kosinski, Jan

AU - Quistgaard, Esben M

AU - Löw, Christian

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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, 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 Å resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 Å 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. Based on 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.

AB - 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, 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 Å resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 Å 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. Based on 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.

U2 - 10.1021/jacs.8b11343

DO - 10.1021/jacs.8b11343

M3 - Journal article

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

ER -