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Structural biology opens new perspectives in the treatment of psychiatric disorders.

Structural biology opens new perspectives in the treatment of psychiatric disorders.

Credit: GlyT1 (light blue) is a protein that transports glycine through the cell membrane (gray) .To do this, it opens alternately to the outside and inside of the cell. In contrast to other neurotransmitters, it is bound by an inhibitor (orange) from the inside of the cell rather than the extracellular sybody, which is a synthetic mini-antibody. (Dark blue) also inhibits GlyT1 by binding to new extracellular sites.credit: Azadeh Shahsavar / DANDRITE.

Glycine is the smallest amino acid, one of the building blocks of proteins. It also acts as a neurotransmitter in the brain, allowing neurons to communicate with each other and modulate neuron function. Several researchers focused on increasing glycine levels in synapses to find an effective treatment for schizophrenia. This can be done by using inhibitors that target Glycine Transporter 1 (GlyT1), a protein that is in neuronal membranes and is responsible for glycine uptake into neurons. However, the development of the drug was hindered because the 3D structure of GlyT1 was unknown.

To examine the structure of GlyT1, researchers from the Danish Institute of Translational Neuroscience (DANDRITE), part of the Nordic EMBL Collaboration for Molecular Medicine, F. Hoffmann-La Roche, EMBL Hamburg, University of Zurich, Aarhus University. , And Linkster Therapeutics joined forces. “This project has required multidisciplinary collaboration and specialized expertise from different laboratories over the years,” said Azadeh Shahsavar, first author of the study and now an assistant professor at DANDRITE. Studying during her time as a postdoc in the EMBL Interdisciplinary Postdocs (EIPOD) program, during her time working at EMBL Hamburg, DANDRITE and Roche.

Poul Nissen, DANDRITE Director and Senior Research Fellow in the Opinion Study: “We are extremely grateful for the EMBL EIPOD program and the Nordic EMBL collaboration that has followed us for a long time and allows us to explore very difficult ways. There is no way to be successful without it, and certainly without Azadeh’s persistence! “

Overcoming Glycine Transporter Study 1 Challenges

GlyT1 has become particularly challenging in studies because it is unstable when extracted from cell membranes. To stabilize it, scientists have combined a number of methods, such as creating more stable proteins. To capture the transporters in a clinically relevant state, the team used a chemical created by Roche to capture and stabilize GlyT1 from the inside and to design an externally-bound synthetic-antibody (sybody) mini-antibody.

Scientists tested 960 different conditions and obtained GlyT1 crystals in one of them. “The crystals were very small and difficult to visualize. We chose to measure results at EMBL Hamburg’s P14 beamline, which is ideal for such a challenging experiment,” Azadeh said. It’s exceptionally strong and focused, and its device has features designed to work with micrometer-sized crystals. But the quality of the crystals fluctuates, which makes collecting data a challenge. Eventually, Azadeh’s persistence was exhausted. “I remember when I first saw the electron density of the inhibitor, I was so excited, I couldn’t sleep for two nights,” she said. “You live for the moment. Those worthwhile “

Credit: Glycine Transporter 3D Molecular Structure 1. GlyT1 (teal) transports glycine through the cell membrane. Unlike most neurotransmitter inhibitors, the inhibitor used in this study (green) binds GlyT1 from the inside of the cell rather than the extracellular sybody inhibitor, a synthetic mini-antibody (pink) also. Inhibit GlyT1 by binding to a new extracellular site.credit: Azadeh Shahsavar / DANDRITE.

The final challenge is data analysis. While crystals provided a weak diffraction pattern due to their small size, intense X-rays destroyed the crystal in less than a second. A single crystal only gave some information about its structure, so Azadeh had to collect information from hundreds of crystals. “Processing massive amounts of data is possible thanks to the unique infrastructure of EMBL Hamburg,” she said. Some of the data sets are complex for existing software, but the Schneider group at EMBL Hamburg writes custom software. For such cases, it allows Azadeh to integrate the dataset into a full image of GlyT1 at 3.4 Å resolution (1 Å or ångström is one ten billionth of a meter, the size of a common atom). With a different scientific background, everyone contributed to their specific expertise that made this study possible, ”Azadeh said.

For Thomas Schneider, Head of Research Infrastructure at EMBL Hamburg, the study is a perfect example that highlights the importance of both scientific excellence and the availability of modern infrastructure for advanced research. “For such a challenging project, we are pleased to bring our employee methodological expertise to work and to fully utilize the technology capabilities of the beam and preparation facilities. The PETRA III synchrotron on the DESY campus and the versatile high-precision diffusion meter, developed in collaboration between EMBL Hamburg, EMBL Grenoble and ARINAX, are key to this project.

Azadeh agrees. “Excellence. The hardware and software infrastructure provided by EMBL is of the highest quality and is continuously improved,” she added.

Blueprints for new therapies

The analysis revealed an unexpected structure of GlyT1, in contrast to other neurotransmitter transporters, which are inhibited by inhibitors from the outside of the cell membrane.GlyT1 is then inhibited by inhibitors from the inside. “The structure came as a surprise to us. It seems that GlyT1 inhibitors must cross the cell membrane before they can reach GlyT1 from within the neuron,” said Roger Dawson, senior author in the study.

“The structure is a blueprint for the development of new GlyT1 inhibitors, either organic molecules or antibodies,” explains Roger. “The sybody developed for this study binds GlyT1 to a previously unknown binding site and locks it.” In a state where glycine can no longer be transported, we can use this knowledge to develop drugs that target not only GlyT1 but also other future membrane transport proteins. ”

Prescribing glycine transporters opens up new avenues for psychiatric drug development.

More information:
Azadeh Shahsavar et al, Structural insights into glycine reabsorption inhibition, nature (2021). DOI: 10.1038 / s41586-021-03274-z.

Provided by the European Laboratory of Molecular Biology.

Reference: Structural biology opens up new perspectives in the treatment of psychiatric disorders (2021, April 6) .Retrieved on April 7, 2021 from https://phys.org/news/2021-04-biology-perspectives-psychiatric-disorders.html

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