In a groundbreaking study, researchers from the Institute of Physics of the Chinese Academy of Sciences, led by Prof. JIANG Daohua, have unraveled the intricacies of the vesicular monoamine transporter protein 2 (VMAT2), shedding light on its role in neurotransmitter transport. Published in Nature, the study provides high-resolution cryo-electron microscopy (cryo-EM) structures of VMAT2 and elucidates the mechanisms of substrate recognition and drug inhibition, with potential implications for drug development.
Due to its small membrane protein structure, neurotransmitters, crucial for various neurological activities, are regulated by VMAT2, a challenging subject for cryo-EM analysis. Overcoming this hurdle, the researchers utilized fusion proteins to obtain high-resolution structures of VMAT2 in different conformations related to its transport cycle.
The study focused on three clinical drugs targeting VMAT2—reserpine, tetrabenazine, and ketanserin—commonly used for treating hypertension and hyperactivity disorders. Cryo-EM structures were determined in cytoplasm-facing, occluded, and lumen-facing states, representing key stages in VMAT2’s transport cycle. This allowed for a comprehensive understanding of substrate recognition and drug inhibition.
The research revealed distinct inhibitory mechanisms of the drugs. For instance, reserpine competes with serotonin for binding to cytoplasm-facing VMAT2, while tetrabenazine and ketanserin stabilize VMAT2 in occluded and lumen-facing states. These findings provide crucial insights into the pharmacological properties of these drugs and their potential implications for treating various disorders.
Furthermore, the study explored the substrate-bound state of VMAT2, specifically serotonin, adopting a lumen-facing conformation. This conformation is favorable for substrate release, enhancing the understanding of VMAT2 functions in neurotransmitter regulation.
The significance of this research extends beyond neurotransmitter regulation, offering a strategy for studying small membrane proteins. The VMAT2 fusion protein strategy employed in the study holds promise for advancing the structural analysis of other membrane transporter proteins and small proteins through cryo-EM.
The study “Transport and inhibition mechanism of human VMAT2” deepens our understanding of VMAT2 functions, opens avenues for drug development, and provides a valuable approach for studying other challenging membrane proteins.
