Journal
SCIENCE ADVANCES
Volume 7, Issue 35, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh3355
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Funding
- Wellcome Trust [201536, 203741]
- EPA Cephalosporin Trust
- Royal Society/Wolfson Foundation Laboratory Refurbishment grant [WL160052]
- High-End Computing Consortium for Biomolecular Simulation (HECBioSim) - EPSRC [EP/T022205/1, EP/R029407/1]
- Wellcome [209194, 100298, 219531, 215519]
- MRC grants [MR/M011984/1, MR/S021043/1]
- EPSRC [EP/L000253/1] Funding Source: UKRI
- MRC [MR/M011984/1, MR/S021043/1] Funding Source: UKRI
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The proton-coupled solute carriers PepT1 and PepT2 in the SLC15 family are crucial for acquiring dietary nitrogen and have extreme substrate promiscuity. Recent studies on their structure and function provide insights into their potential applications in drug development.
The SLC15 family of proton-coupled solute carriers PepT1 and PepT2 play a central role in human physiology as the principal route for acquiring and retaining dietary nitrogen. A remarkable feature of the SLC15 family is their extreme substrate promiscuity, which has enabled the targeting of these transporters for the improvement of oral bioavailability for several prodrug molecules. Although recent structural and biochemical studies on bacterial homologs have identified conserved sites of proton and peptide binding, the mechanism of peptide capture and ligand promiscuity remains unclear for mammalian family members. Here, we present the cryo-electron microscopy structure of the outward open conformation of the rat peptide transporter PepT2 in complex with an inhibitory nanobody. Our structure, combined with molecular dynamics simulations and biochemical and cell-based assays, establishes a framework for understanding peptide and prodrug recognition within this pharmaceutically important transporter family.
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