Structural highlights
FunctionPEPT_YERP4 Mediates the proton-dependent uptake of dipeptides. Shows higher affinity for dipeptides with a negatively charged amino acid residue at the N-terminal position, such as Asp-Ala and Glu-Ala. Also displays specificity for Ala-Ala, Ala-Tyr and Tyr-Ala.[1] Publication Abstract from PubMedInhibitors for membrane transporters have been shown to be indispensable as drugs and tool compounds. The proton-dependent oligopeptide transporters PEPT1 and PEPT2 from the SLC15 family play important roles in human and mammalian physiology. With Lys[Z(NO(2))]-Val (LZNV), a modified Lys-Val dipeptide, a potent transport inhibitor for PEPT1 and PEPT2 is available. Here we present the crystal structure of the peptide transporter YePEPT in complex with LZNV. The structure revealed the molecular interactions for inhibitor binding and a previously undescribed mostly hydrophobic pocket, the PZ pocket, involved in interaction with LZNV. Comparison with a here determined ligand-free structure of the transporter unveiled that the initially absent PZ pocket emerges through conformational changes upon inhibitor binding. The provided biochemical and structural information constitutes an important framework for the mechanistic understanding of inhibitor binding and action in proton-dependent oligopeptide transporters. Peptide transporter structure reveals binding and action mechanism of a potent PEPT1 and PEPT2 inhibitor.,Stauffer M, Jeckelmann JM, Ilgu H, Ucurum Z, Boggavarapu R, Fotiadis D Commun Chem. 2022 Feb 24;5(1):23. doi: 10.1038/s42004-022-00636-0. PMID:36697632[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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