Glycine can stimulate or inhibit neurons in the brain, thereby controlling complex functions. In order to clarify the three-dimensional structure of the glycine transporter, researchers have now taken another big step towards understanding the regulation of glycine in the brain. The results published in the journal Nature provide an opportunity to find effective drugs that inhibit the function of GlyT1. These drugs are of great significance for the treatment of schizophrenia and other mental diseases.
Glycine is the smallest amino acid, a component of protein, and a key neurotransmitter that can stimulate or inhibit neurons in the brain to control complex brain functions. The termination of the glycine signal is mediated by a glycine transporter, which re-uptakes and clears glycine from the synapses between neurons. The glycine transporter GlyT1 is the main regulator of the neurotransmitter glycine level in the brain and is also important for blood cells. In blood cells, glycine is required for the synthesis of heme.
The N-methyl-D-aspartate (NMDA) receptor is activated by glycine, and its poor performance is related to schizophrenia. Therefore, in the past 20 years, many pharmaceutical companies and academic research laboratories have focused their attention on influencing glycine signaling and glycine reuptake delay as a way to activate NMDA receptors to find schizophrenia and Treatment of other mental illnesses.
Indeed, several effective and selective GlyT1 inhibitors can achieve antipsychotic and cognition-promoting effects that alleviate many symptoms of schizophrenia, and have entered clinical trials. However, no successful drug candidates have emerged, and the inhibition of GlyT1 in blood cells is a concern for side effects. The structural insights of the combination of inhibitors and GlyT1 will provide insights for finding new strategies for drug design.
In order to better understand the three-dimensional structure and inhibitory mechanism of the GlyT1 transporter, from Roche and Linkster, as well as the European Molecular Biology Laboratory (EMBL) at the University of Hamburg, Zurich and Aarhus ) In collaboration with the researchers. One of the most advanced GlyT1 inhibitors.
Using a synthetic single domain antibody (Linkstertherapy’sybody®) against GlyT1, the research team managed to grow microcrystals of the inhibited GlyT1 complex. A team led by Assistant Professors Azadeh Shahsavar and Professor Poul Nissen of the Department of Molecular Biology and Genetics/DANDRITE at Aarhus University uses the serial synchrotron crystallography (SSX) method to utilize hundreds of microcrystals. The SSX method is particularly suitable for use as a powerful new X-ray source method, and opens up new methods such as drug development for various purposes.
This structure was reported in the leading scientific journal “Nature” and also revealed a new mechanism that generally inhibits neurotransmitter transporters. Previously, mechanisms such as the use of antidepressants to inhibit the serotonin transporter (which has many similarities with GlyT1) have been discovered, but what has now been discovered is a completely different inhibitory mechanism from GlyT1.
It provides background knowledge for the further development of small molecules and antibodies. These small molecules and antibodies are selective inhibitors of GlyT1, and may also provide new ideas for the development of other neurotransmitter carrier inhibitors that can be used to treat other mental diseases. Knowledge. Azadeh Shahsavar’s team continues to conduct research on GlyT1 and will study its function and inhibitory effects as well as other aspects of the role of GlyT1 inhibitors in the body.
Tags: amino acids, antibodies, antibodies, antidepressants, antipsychotics, blood, brain, crystallography, diffraction, drugs, genetics, glycine, laboratory, medicine, molecular biology, neurons, neuroscience, receptors, Research, schizophrenia, serotonin, therapeutics, x-ray
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Post time: Mar-12-2021