Neurons talk to each other using chemical signals called neurotransmitters. Scientists at St. Jude Children's Research Hospital have drawn on structural biology expertise to determine structures of vesicular monoamine transporter 2 (VMAT2), a key component of neuronal communication.
Reviewed by Danielle Ellis, B.Sc.Nov 2 2023 By visualizing VMAT2 in different states, scientists now better understand how it functions and how the different shapes the protein takes influence drug binding -; critical information for drug development to treat hyperkinetic disorders such as Tourette syndrome. The work was published today in Nature.
VMATs are transporters that are required for packing these monoamine neurotransmitters into synaptic vesicles." Once the VMAT has packed the vesicle with monoamines, the "cargo ship" moves towards the synaptic gap , where it releases the chemical compounds. Despite their importance, the structure of VMAT2, which would allow researchers to investigate how it works fully, had remained elusive. Lee and his team used cryo-electron microscopy to obtain structures of VMAT2 bound to the monoamine serotonin and the drugs tetrabenazine and reserpine, which are used to treat chorea and hypertension, respectively. This was no easy feat.
Answering a 40-year-old question The researchers discovered this dynamic mechanism means multiple opportunities for drugs to bind. They confirmed that reserpine and tetrabenazine bind two different conformations of VMAT2. "30 or 40 years of pharmacological research had suggested that these two drugs bind to the transporter in different ways," said Pidathala, "but nobody knew the atomic details of how this works.
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Scientists reveal structures of neurotransmitter transporterNeurons talk to each other using chemical signals called neurotransmitters. Scientists at St. Jude Children's Research Hospital have drawn on structural biology expertise to determine structures of vesicular monoamine transporter 2 (VMAT2), a key component of neuronal communication.
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