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Structural biology opens up new perspectives on the treatment of psychiatric disorders

Structural biology opens up new perspectives on 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. Unlike other neurotransmitter transporters, it is bound by its inhibitor (orange) from the intracellular side rather than the extracellular one. Sybodyen, a synthetic mini-antibody (dark blue), also inhibits GlyT1 by binding to a new extracellular site. 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 neuronal activity. Many researchers have focused on increasing glycine levels in synapses to find an effective treatment for schizophrenia. This could be done using inhibitors that target glycine transporter 1 (GlyT1), a protein that sits in neuronal cell membranes and is responsible for the uptake of glycine into neurons. However, the development of such drugs is inhibited because the 3D structure of GlyT1 was not known.

To determine the structure of GlyT1, researchers at the Danish Research Institute for Translational Neuroscience (DANDRITE), which is part of the Nordic EMBL partnership for molecular medicine, F. Hoffmann-La Roche, EMBL Hamburg, University of Zurich, Aarhus University , and Linkster Therapeutics merged. “This project required interdisciplinary collaboration and unique expertise from different laboratories over several years,” said Azadeh Shahsavar, first author of the study and now assistant professor at DANDRITE. She performed the measurements for the study during her time as a postdoc in the EMBL Interdisciplinary Postdocs (EIPOD) program, where she worked at EMBL Hamburg, DANDRITE and Roche.

Poul Nissen, director of DANDRITE and senior researcher in the study, comments: “We are incredibly grateful to EMBL’s EIPOD scheme and the Nordic EMBL partnership for keeping us on track for so long and giving us the opportunity to explore very difficult approaches. We would have not succeeded without it, and without Azadeh’s persistence of course! “

Overcoming challenges in the study of glycine transport 1

GlyT1 proved to be particularly challenging to study because it is unstable when extracted from the cell membrane. To stabilize it, researchers combined several approaches, such as creating more stable variants of the protein. To capture the transporter in a clinically relevant state, the team used a chemical created by Roche that binds and stabilizes GlyT1 from the inside and designed a synthetic mini-antibody (sybody) that binds it from the outside.

The researchers tested 960 different conditions and managed to obtain GlyT1 crystals in one of them. “The crystals were very small and difficult to image. We chose to measure them at EMBL Hamburg’s jet line P14, which is suitable for challenging experiments like this,” says Azadeh. The X-ray beam on the P14 is particularly strong and focused, and its equipment has features tailored to work with even crystals in micrometer size. Nevertheless, the quality of the crystals was variable, which made data collection challenging. In the end, Azadeh’s perseverance paid off. “I remember when I saw the electron density of the inhibitor for the first time. I was so excited that I could not sleep for two nights,” she says. “You live for the rewarding moments.”

Credit: 3D molecular structure of glycine transporter 1. GlyT1 (teal) transports glycine through the cell membrane. Unlike inhibitors of most neurotransmitter transporters, the inhibitor used in this study (green) binds GlyT1 from the intracellular side rather than the extracellular one. Sybodyen, a synthetic mini-antibody (pink), also inhibits GlyT1 by binding to a new extracellular site. Credit: Azadeh Shahsavar / DANDRITE

The last challenge was the data analysis. While the crystals gave only weak diffraction patterns due to their small size, the strong X-rays destroyed crystals in less than a second. A single crystal would only provide partial information about the structure, so Azadeh had to collect data from hundreds of crystals. “Processing such an enormous amount of data was possible thanks to the unique infrastructure of EMBL Hamburg,” she says. The combination of partial datasets was complex for the existing software, but the Schneider group at EMBL Hamburg wrote software specifically designed for such cases. It allowed Azadeh to merge datasets into a complete image of GlyT1 with a resolution of 3.4 Å (1 Å or angstroms is ten billionths of a meter – about the size of a typical atom). “I really enjoyed working with people with different scientific backgrounds. Everyone contributed with their unique expertise that made this study possible,” says Azadeh.

For Thomas Schneider, Joint Head of Research Infrastructures at EMBL Hamburg, the study is a perfect example highlighting the importance of both scientific excellence and the availability of groundbreaking infrastructures for research progress. “For challenging projects such as this, we are pleased to bring our staff’s methodological expertise to work and take full advantage of the technological capabilities of our beam lines and sample preparation facilities. The high-intensity micro-focused beam produced by the PETRA III synchrotron on the DESY campus and the versatile diffractometer with high precision developed in a collaboration between EMBL Hamburg, EMBL Grenoble and ARINAX was the key to this project. “

Azadeh agrees. “Excellence, infrastructure, hardware and software provided by EMBL are of the highest quality and they are constantly improving,” she adds.

Blueprint for new drugs

The analysis revealed an unexpected structure of GlyT1. Unlike other neurotransmitter transporters, which are bound by their inhibitors from the outer side of the cell membrane, GlyT1 is bound by its inhibitor from the inner side. “The structure was a surprise to us. It appears that the GlyT1 inhibitor must first cross cell membranes before it can access GlyT1 from within the neurons,” said Roger Dawson, a senior author of the study.

“This structure provides a plan for the development of new inhibitors of GlyT1, whether it be organic molecules or antibodies,” Roger explains. The sybody developed for this study binds GlyT1 at a previously unknown binding site and locks it in a state where it can no longer transport glycine. We could use this knowledge to develop drugs that not only target GlyT1, but also other membrane transport proteins in the future. ”

Determination of glycine transporter opens new avenues in the development of psychiatric drugs

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

Provided by the European Molecular Biology Laboratory

Citation: Structural Biology Opens New Perspectives for the Treatment of Psychiatric Disorders (2021, April 6) Retrieved April 7, 2021 from https://phys.org/news/2021-04-biology-perspectives-psychiatric-disorders.html

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