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Structural biology opens up new prospects for the treatment of mental illness



Structural biology opens up new prospects for the treatment of mental illness

Credit: GlyT1 (light blue) is a protein that transports glycine (grey) on the cell membrane. To this end, it alternately opens to the inside and outside of the unit. In contrast to other neurotransmitter transporters, it is bound by the inhibitor (orange) inside the cell rather than outside the cell. Sybody is a synthetic mini-antibody (dark blue) that also inhibits GlyT1 by binding to new extracellular sites. Image credit: Azadeh Shahsavar / DANDRITE

Glycine is the smallest amino acid and one of the components of protein. It also acts as a neurotransmitter in the brain, allowing neurons to communicate with each other and regulating neuronal activity. Many researchers are working to increase the level of glycine in synapses to find effective treatments for schizophrenia. This can be done by using inhibitors against glycine transporter 1 (GlyT1), which is located in the cell membrane of neurons and is responsible for the uptake of glycine by neurons. However, the lack of knowledge of the 3D structure of GlyT1 hinders the development of this drug.

In order to determine the structure of GlyT1, researchers from the Danish Institute for Translational Neuroscience (DANDRITE), a member of the Nordic EMBL Molecular Medicine Cooperation Organization, F. Hoffmann-La Roche, Hamburg EMBL Hamburg, University of Zurich, University of Aarhus, and Linkster Therapeutics teamed up. The first author of the study, Azadeh Shahsavar, currently assistant professor at DANDRITE, said: “This project requires several years of multidisciplinary cooperation and unique expertise from different laboratories.” She served as a postdoctoral fellow in the EMBL Interdisciplinary Postdoctoral (EIPOD) program. During this period, she conducted measurements for this research. During this period, she worked in Hamburg EMBL, DANDRITE and Roche.

Poul Nissen, Director of DANDRITE and senior researcher of this research, said: “We are very grateful to EMBL’s EIPOD program and the Nordic EMBL partnership, which allowed us to persevere for a long time and allowed us to explore very difficult methods. We will not have it, and of course we will not Azadeh’s persistence will not succeed!”

Overcoming the challenge of studying glycine transporter 1

It turns out that the study of GlyT1 is particularly challenging because it is unstable when extracted from the cell membrane. To stabilize it, scientists have combined several methods, such as creating more stable variants of the protein. In order to make the transporter in a clinically relevant state, the research team used a chemical reagent manufactured by Roche, which binds and stabilizes GlyT1 from the inside, and designed a synthetic mini-antibody that binds to GlyT1 from the outside. (Sybody).

Scientists tested 960 different conditions and managed to obtain GlyT1 crystals under one of them. Azadeh said: “The crystal is very small and difficult to image. We chose to measure it on the beamline P14 of the Hamburg EMBL, which is very suitable for such challenging experiments.” The X-ray beam at P14 is particularly strong and focused, and its equipment It has a function specially tailored for processing micron-level crystals.​​ However, the quality of the crystal is variable, which makes data collection challenging. In the end, Azad’s perseverance paid off. She said: “I remember the first time I saw the electron density of an inhibitor. I was so excited that I couldn’t sleep for two nights.” “You live for those meaningful moments.”







Source: 3D molecular structure of Glycine Transporter 1. GlyT1 (vial) transports glycine through the cell membrane. Unlike most inhibitors of neurotransmitter transporters, the inhibitor (green) used in this study binds GlyT1 from the inside of the cell rather than the outside of the cell. Sybody, a synthetic mini-antibody (pink), also inhibits GlyT1 by binding to new extracellular sites. Image credit: Azadeh Shahsavar / DANDRITE

The final challenge is data analysis. Although they only give a weak diffraction pattern due to the small size of the crystals, the strong X-rays destroy the crystals in less than a second. Single crystals only produce partial information about the structure, so Azadeh must collect data from hundreds of crystals. She said: “Thanks to the unique infrastructure of Hamburg EMBL, it can handle such a large amount of data.” For existing software, merging part of the data set is very complicated, but the Schneider group of Hamburg EMBL has written a special design for such situations. Software. It enables Azadeh to merge the data set into a complete picture of GlyT1 with a resolution of 3.4Å (1Å or ångström, equal to one billionth of a meter, approximately the size of a typical atom). Azadeh said: “I really enjoy working with people with different scientific backgrounds. Everyone has contributed their unique expertise to make this research possible.”

For Thomas Schneider, co-head of research infrastructure at EMBL in Hamburg, this study is a perfect example of the importance of scientific excellence and the importance of the availability of cutting-edge infrastructure for conducting research. “For challenging projects like this, we are happy to use the methodological expertise of our employees and make full use of the technical capabilities of our beam lines and sample preparation equipment. The high-intensity micro-focused beam generated by the PETRA III synchrotron The DESY campus and the multifunctional high-precision diffractometer jointly developed by Hamburg EMBL, Grenoble EMBL and ARINAX are the key to this project.”

Azadeh agreed. She added: “The excellence provided by EMBL, the infrastructure, hardware and software are of the highest quality and will continue to be improved.”

Blueprint for new treatments

The analysis revealed an unexpected structure of GlyT1. It binds to other neurotransmitter transporters through inhibitors on the outside of the cell membrane, and GlyT1 binds from the inside through its inhibitors. The senior author of the study Roger Dawson said: “This structure is a surprise to us. It seems that GlyT1 inhibitors must first pass through the cell membrane to enter GlyT1 from the inside of the neuron.”

Roger explained: “This structure provides a blueprint for the development of new GlyT1 inhibitors, whether they are organic molecules or antibodies.” “The sybody developed for this research binds GlyT1 at a previously unknown binding site and combines it Locked in a state where glycine can no longer be transported. We can use this knowledge to develop future drugs that target not only GlyT1 but also other membrane transporters.”


The determination of glycine transporter opens up a new way for the development of psychotropic drugs


More information:
Azadeh Shahsavar et al., “Structural Insights on Inhibition of Glycine Reuptake”, natural (2021). DOI: 10.1038 / s41586-021-03274-z

Provided by European Molecular Biology Laboratory



Citation: Structural biology opens up a new perspective for the treatment of mental illness (April 6, 2021). The study was launched on April 7, 2021 from https://phys.org/news/2021-04-biology-perspectives- psychiatric-disorders.html search

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