Peptide transporter structure reveals binding and action mechanism of a potent PEPT1 and PEPT2 inhibitor

Stauffer, Mirko; Jeckelmann, Jean-Marc; Ilgü, Hüseyin; Ucurum, Zöhre; Boggavarapu, Rajendra; Fotiadis, Dimitrios (2022). Peptide transporter structure reveals binding and action mechanism of a potent PEPT1 and PEPT2 inhibitor. Communications chemistry, 5(1) Springer Nature 10.1038/s42004-022-00636-0

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Inhibitors 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(NO2)]-
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.

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