3/28/2023 0 Comments Embr tungsten rings![]() To address this question, we determined high-resolution crystal structures of a bacterial homologue to the mammalian PepT1 protein from Streptococcus thermophilus, PepT St in complex with physiologically relevant di- and tripeptides in addition to a peptide-free apo form (Table 1). ![]() Conserved pairs of salt bridge interactions coordinate structural rearrangements that lead to the vectorial co-transport of peptides and protons across the membrane 3 11.Ī key question we sought to address was how one binding site could specifically recognize and transport such a large number of different ligands, while retaining specificity for peptides only two or three amino acids long. A centrally located peptide-binding site is highly conserved between prokaryote and eukaryote members, with both operating via similar transport mechanisms 13. The POT/PTR family contains a number of conserved sequence motifs ( Supplementary Fig S1) and a conserved architecture consisting of 12 or 14 transmembrane α-helices arranged into N (H1–6)- and C-terminal (H7–12) bundles 3 10 11 12. The POT (or PTR) family belongs to the major facilitator superfamily (MFS) of secondary active transporters that includes the OATPs, OATs and OCTs 7 8 9. They are of increasing pharmaceutical importance as they recognize and transport a growing library of antibiotics, antiviral and anticancer molecules 6. The human POT family transporters, PepT1 (SLC15A1) and PepT2 (SLC15A2), are responsible for peptide transport across the plasma membrane and have evolved one of the most promiscuous binding sites in biology, capable of recognizing and transporting over 8,000 different di- and tripeptide ligands 5. The molecular basis for this promiscuity or polyspecificity is an important biochemical question that must be addressed if their role in drug transport is to be understood and usefully exploited. These include the organic anion-transporting polypeptides (OATPs), the organic anion and cation transporters (OAT and OCT) and the proton-coupled peptide transporters (POT/PTR family) 3 4. However, a number of mammalian nutrient transporters also recognize and transport a variety of drug molecules, in addition to their intended nutrients, with important implications for drug pharmacokinetics and drug–drug interactions 2. Membrane transporters involved in nutrient uptake are usually substrate specific, recognizing and transporting only chemically very similar ligands across the membrane 1.
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