From Binding to Transport: DtpB’s Complex Interaction with Peptides

Proton-dependent oligopeptide transporters play a vital role in allowing a variety of dietary peptides and orally taken peptidomimetic drugs to enter cells. Given their clinical and pathophysiological significance, these transporters are extensively studied nowadays, yet the exact way they recognize and transport different types of peptides is not completely understood.

In a very recent study published in Cell Reports, Kotov et al. looked at how the bacterial transporter DtpB interacts with different peptides, aiming to understand the relationship between binding strength and transport efficiency. The authors used various techniques, including thermal unfolding assay, pyranine-based uptake assays as well as peptide transport assay using the SURFE2R. They analyzed the crystal structures of DtpB complexed with 14 different peptides, measured how tightly different peptides bind to DtpB, and tested how well DtpB transports these peptides. Additionally, they employed computer simulations to predict how thousands of different peptides might interact with DtpB.

The researchers found that DtpB can interact with a wide variety of peptides and that those with certain properties, like compact hydrophobic residues, tend to bind more strongly to DtpB. Strong binding, however, doesn’t mean efficient transport. The authors showed that only mid-affinity peptides are well transported by DtpB in a reconstituted system; high-affinity peptides were only poorly transported and rather act as inhibitors. The researchers speculated that this might be a common trait of promiscuous transporters, that transport a wide range of molecules.

The authors suggested that their findings could be used to develop new strategies for drug design. For example, they proposed that some peptides that were thought to be taken up by a human protein called PepT1 in the gut might actually act as inhibitors, potentially useful for treating inflammatory bowel disease and colon cancer.

Overall, this study gives valuable insights into how DtpB interacts with peptides and could help in designing drugs that interact with similar proteins in the future.

Read the article here.

Learn more about Solid Supported Membrane-Based Electrophysiology and SURFE²R devices here.