Promiscuous protein structure will help scientists design better drugs

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Scientists at EMBL Hamburg and CSSB have determined the molecular structure of an intestinal protein that helps us absorb many drugs. This could help develop drugs that reach target tissues more effectively.

The human peptide transporter PepT1 transports digested proteins from the intestine to the bloodstream. PepT1 also carries many drugs, including antibiotics and antivirals. The structure of PepT1 in the picture is based on the PDB inputs: 7PMW, 7PMX, 7PMY and 7PN1. Credit: Isabel Romero Calvo / EMBL

During digestion, the proteins we eat are broken down into smaller pieces called peptides, which are made up of amino acids that our bodies later use to build their own proteins. Before this can happen, the peptides must first be transported from the intestine to the bloodstream. This task is performed by a molecule called peptide transporter 1 (PepT1), which is found in the cell membrane of the intestinal wall and moves small peptides across the cell membrane.

In the human body, there are around 800 transport systems dedicated to different kinds of nutrients. Most of them are very specialized. For example, some sugar carriers can only absorb one type of sugar. However, PepT1 is different – it can transport almost any type of short peptide. In scientific jargon, this ability is called “promiscuity”.

Group leader Christian Löw is EMBL Hamburg’s expert on membrane proteins. His group, in collaboration with colleagues from the Center for Structural Systems Biology (CSSB) and the Universitätsklinikum Hamburg-Eppendorf (UKE), determined the molecular structures of human PepT1 and its relative PepT2, which is present primarily in the kidney. for the absorption of nutrients. Scientists used electron cryomicroscopy, a technique in which frozen samples are imaged using electrons instead of light.

New possibilities for improving drug design

The promiscuity of PepT1 allows it to transport not only nutrient peptides but also various types of drugs, including certain antibiotics, antivirals, and blood pressure medications. However, PepT1 transports drugs less efficiently than it does transport many natural peptides. As a result, only a fraction of the drugs we consume ends up in our bloodstream. The rest remains in the intestine, which can lead to various side effects. Increasing the dosage of drugs to compensate for inefficient transport is particularly dangerous in the case of antibiotics, as it can lead to the generation of antibiotic resistant bacteria.

“Now that we know what the structure of PepT1 looks like, it will be possible to design new drugs that harness PepT1 to cross the intestinal wall much more efficiently than before,” Löw said. “The structure of human PepT1 will allow us to improve drug design by making absorption more efficient. Currently, it is almost impossible to predict whether a drug candidate can pass through the intestinal wall via this transport system. Until now, obtaining such a drug has been very difficult. Many potentially effective drug candidates have failed in preclinical studies because they were poorly absorbed. With the help of the structural information for PepT1, some of these failed candidates could be redesigned so that they can be transported efficiently by PepT1. Likewise, many existing drugs could be modified to improve their absorption.

Watch the transporter in stop-motion

The molecular structure of human PepT1 is among the smallest structures determined by electron cryomicroscopy. It looks like a forceps open towards the inside of the intestine. When a peptide binds to PepT1, the clamp closes around it and then opens to the other side of the membrane to release it. Scientists not only determined the structure of the transporter, but even captured it in various states throughout the transport cycle.

“We visualized the entire transport process in molecular detail, like in a movie,” said Maxime Killer, lead author of the study. “Membrane proteins are notoriously difficult to study, but we hope the tips we have developed to study PepT1 will help other scientists to solve similar protein structures in the future.”

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