Structure of a 'promiscuous' protein will help scientists design better drugs

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Researchers at CSSB and EMBL Hamburg have identified the molecular structure for a gut protein that aids in drug absorption. This information could be used to help develop drugs that target more tissues.

The proteins we eat get broken down into smaller pieces called peptides. These peptides are made up of amino acids which our bodies later use to make new proteins. The peptides must first be transferred from the gut into the bloodstream. A molecule called peptidetransporter 1 (PepT1) performs this task and moves small peptides through the cell membrane.

There are approximately 800 transport systems in the body that can be used to transport different types of nutrients. Many of these systems are highly specialized. Some sugar transporters, for example, can only take up one type of sugar. PepT1 can transport nearly any short peptide. This ability is known as "promiscuity" in scientific jargon.

Christian Lw, Group Leader at EMBL Hamburg is an expert in membrane proteins. His group has been working with colleagues from the Centre for Structural Systems Biology and the Universittsklinikum Hamburg-Eppendorf (UKE) to determine the molecular structure of human PepT1 (and its relative PepT2), which are mainly found in the kidney for nutrient resorption. Cryo-electron microscopic microscopy is a technique that uses electrons to image frozen samples.

PepT1 is a human peptide transporter that transports digested protein from the gut to the bloodstream. PepT1 can also transport many drugs, such as antibiotics and antivirals. Based on the PDB entries 7PMW, 7PMX and 7PMY, the structure of PepT1 is shown in the image. Credit: Isabel Romero Calvo / EMBL

There are new ways to improve drug design

PepT1's promiscuity allows it to transport not just nutritious peptides, but also many types of drugs, including antivirals and drugs for hypertension. PepT1 is able to transport drugs more efficiently than many natural peptides. Only a small fraction of drugs we take in make it into our bloodstream. Rest of the drugs remain in the stomach, which can lead to side effects. In the case of antibiotics it is especially dangerous to increase the dose to compensate for poor transport. This could lead to antibiotic-resistant bacteria.

Lw. said, "Now that we have a better understanding of the structure of PepT1, it will be possible for us to design new drugs that exploit PepT1's ability to cross the intestinal wall more efficiently than ever before." Lw stated that the structure of human PepT1 will enable us to improve drug design and make absorption more efficient. It's difficult to predict whether a candidate drug can cross the gut wall using this transport system. This has made it difficult to obtain such a drug. Preclinical studies have shown that many potential drug candidates were not well absorbed and failed to prove their effectiveness. Some of these failed candidates could be redesign with the help of PepT1's structural information so they can be efficiently transported by PepT1. Many existing drugs could also be modified to increase their absorption.

Stop-motion video of the transporter

Human PepT1's molecular structure is one of the most small structures that can be determined using cryo-electron microscopic. It looks like a clamp that opens towards the gut. The clamp opens towards the opposite side of the membrane and releases the peptide that has bound to PepT1. Scientists not only identified the structure of the transporter, but also captured it in different states during the transport cycle.

Maxime Killer was the first author of this study. "Membrane protein structures are notoriously hard to study. However, we hope that the techniques we used to study PepT1 can help scientists solve similar structures in the future."

Further X-rays reveal the layout of a drug transporter loaded with drugs

Information: Maxime Killer and colleagues, Structural snapshots from human PepT1 (and PepT2) reveal mechanistic insights into substrate- and drug transport across epithelial cells, Science Advances (2021). Journal information: Science Advances Maxime Killer et al, Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes,(2021). DOI: 10.1126/sciadv.abk3259