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Cited by 20Drug Transport and Resistance MechanismsEnzyme Structure and FunctionAmino Acid Enzymes and Metabolism

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Plasticity of the binding pocket in peptide transporters underpins promiscuous substrate recognition

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Kotov, Vadim, Killer, Maxime, Jungnickel, Katharina E.J., Lei, Jian, Finocchio, Giada, Steinke, Josi, Bartels, Kim, Strauss, Jan, Dupeux, Florine, Humm, Anne-Sophie, Cornaciu, Irina, Márquez, José A., Pardon, Els, Steyaert, Jan, Löw, Christian·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112831

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Abstract

Proton-dependent oligopeptide transporters (POTs) are promiscuous transporters of the major facilitator superfamily that constitute the main route of entry for a wide range of dietary peptides and orally administrated peptidomimetic drugs. Given their clinical and pathophysiological relevance, several POT homologs have been studied extensively at the structural and molecular level. However, the molecular basis of recognition and transport of diverse peptide substrates has remained elusive. We present 14 X-ray structures of the bacterial POT DtpB in complex with chemically diverse di- and tripeptides, providing novel insights into the plasticity of the conserved central binding cavity. We analyzed binding affinities for more than 80 peptides and monitored uptake by a fluorescence-based transport assay. To probe whether all 8400 natural di- and tripeptides can bind to DtpB, we employed state-of-the-art molecular docking and machine learning and conclude that peptides with compact hydrophobic residues are the best DtpB binders.

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Metadata

Authors
Kotov, V., Killer, M., Jungnickel, K. E. J., Lei, J., Finocchio, G., Steinke, J., Bartels, K., Strauss, J., Dupeux, F., Humm, A.-S., Cornaciu, I., Márquez, J. A., Pardon, E., Steyaert, J., & Löw, C.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • Heidelberg University (DE)
  • Sichuan University (CN)
  • European Molecular Biology Laboratory (FR)
  • Vrije Universiteit Brussel (BE)
Corresponding author
Löw, Christian
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-08
Volume
42
Issue
8
Pages
112831
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.112831
OpenAlex
W4384820608
Cited by
20
References
4
Citations by year
2026: 3 · 2025: 5 · 2024: 10 · 2023: 2
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron)
Funders
  • European Commission (847543, 653706, HORIZON2020, 871037)
  • Fonds Wetenschappelijk Onderzoek
  • Deutsches Elektronen-Synchrotron
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
peptide transporters, major facilitator superfamily, substrate recognition, peptide absorption, hydrophobic residues, molecular docking
MeSH terms
Models, Molecular, Peptides, Membrane Transport Proteins, Molecular Docking Simulation

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