Structural insights into substrate recognition in proton-dependent oligopeptide transporters

Area of Science:

• Biochemistry
• Structural Biology
• Membrane Transport

Background:

• Proton-dependent oligopeptide transporters (POTs) facilitate the transport of short-chain peptides across cell membranes.
• POTs are a subfamily of the major facilitator superfamily (MFS).
• Human POTs (PEPT1, PEPT2) are crucial for drug absorption and cellular uptake.

Purpose of the Study:

• To elucidate the structure of an oligomeric POT transporter.
• To understand the mechanism of peptide and drug transport via POTs.
• To provide structural insights applicable to human POTs.

Main Methods:

• X-ray crystallography was used to determine the structure of the Shewanella oneidensis POT transporter (PepTSo2).
• The transporter was crystallized in complex with the peptidomimetic alafosfalin.
• Structural analysis focused on the inward-open conformation.

Main Results:

• The structure of the oligomeric PepTSo2 transporter in an inward-open state was determined.
• The binding site for alafosfalin was identified, revealing conserved ligand-binding residues.
• The structural data provides a template for understanding POT transporter function.

Conclusions:

• The solved structure of PepTSo2 offers a detailed view of POT transporter architecture.
• Highly conserved ligand-binding residues suggest similar transport mechanisms across species.
• These findings have implications for the design of drugs targeting human PEPT1 and PEPT2 transporters.