Multispecific Substrate Recognition in a Proton-Dependent Oligopeptide Transporter

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Transport

Background:

• Proton-dependent oligopeptide transporters (POTs) facilitate the uptake of dietary peptides and are crucial for drug absorption in humans.
• The structural mechanisms by which POTs accommodate diverse peptide side chains remain largely unknown.

Purpose of the Study:

• To elucidate the structural basis of substrate accommodation in proton-dependent oligopeptide transporters.
• To investigate the binding interactions of PepT_St with various dipeptides.

Main Methods:

• Screening of 28 peptides for binding to PepT_St from Streptococcus thermophilus.
• Determination of crystal structures of PepT_St in complex with four distinct dipeptides (Ala-Leu, Phe-Ala, Ala-Gln, Asp-Glu).
• Analysis of binding site residue and water molecule movements, and peptide positioning.

Main Results:

• PepT_St binds four diverse dipeptides with millimolar affinity.
• Structural data reveal that PepT_St accommodates different peptide side chains through dynamic adjustments of binding site residues and water molecules.
• Peptide positioning within the binding site also contributes to optimal fit.

Conclusions:

• PepT_St exhibits significant adaptability in accommodating diverse peptide side chains.
• Understanding these structural adaptations provides insights into the broader mechanisms of peptide transport and drug delivery via POTs.