A research team led by Yan Zhao from the Institute of Biophysics, Chinese Academy of Sciences, has made significant progress in the study of antipsychotic drugs. They have elucidated for the first time the substrate recognition of glycine transporter GlyT1 and the mechanisms by which three antipsychotic drug candidates selectively inhibit GlyT1. Their findings were published in the journal Cell on March 20th.
Schizophrenia is a highly debilitating mental disorder affecting approximately 1% of the global population. GlyT1 is considered a key target for schizophrenia treatment. However, drugs targeting GlyT1 for schizophrenia treatment are still in clinical trials. Investigating GlyT1 substrate recognition, ion binding, conformational changes, and structure-activity relationships with other clinical trial drugs can accelerate the development of GlyT1-targeted drugs.
Using cryo-electron microscopy (cryo-EM), the research team captured the substrate glycine bound to the inward-facing wild-type GlyT1 structure at a resolution of 2.6 Å. They also identified the binding sites for a cotransported chloride ion and two sodium ions, elucidating the coupling between substrate and ion binding and transport. By comparing the central binding cavity and ion binding sites of other neurotransmitter transporters, the team identified key differential residues. They functionally characterized the conserved and differential residues that constitute the substrate and ion binding pockets of GlyT1.
Additionally, the researchers solved two additional conformations of GlyT1 during the transport process and determined the binding sites of three clinical trial drugs: the creatine-based inhibitor ALX-5407 and the non-creatine-based inhibitors SSR504734 and PF-03463275. This is the first study to elucidate the mechanisms by which these three antipsychotic drug candidates selectively inhibit GlyT1.
Furthermore, by comparing the cryo-EM structures of the outward-facing, occluded, and inward-facing conformations, the team systematically described the key interaction networks that stabilize the outward-facing and inward-facing conformations, respectively, enriching our understanding of the conformational change mechanisms of neurotransmitter transporters.
Related Article:
