Nature Structural & Molecular Biology, 13 January, 2025, DOI：https://doi.org/10.1038/s41594-024-01462-9

Binding mechanism and antagonism of the vesicular acetylcholine transporter VAChT

Qiao Ma, Kunpeng Ma, Yanli Dong, Yufei Meng, Jun Zhao, Renjie Li, Qinru Bai, Di Wu, Daohua Jiang, Jianyuan Sun & Yan Zhao

Abstract

The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. Dysregulation of its function can result in neurological disorders. It also serves as a target for developing radiotracers to quantify cholinergic neuron deficits in neurodegenerative conditions. Here we unveil the cryo-electron microscopy structures of human VAChT in its apo state, the substrate acetylcholine-bound state and the inhibitor vesamicol-bound state. These structures assume a lumen-facing conformation, offering a clear depiction of architecture of VAChT. The acetylcholine-bound structure provides a detailed understanding of how VAChT recognizes its substrate, shedding light on the coupling mechanism of protonation and substrate binding. Meanwhile, the vesamicol-bound structure reveals the binding mode of vesamicol to VAChT, laying the structural foundation for the design of the next generation of radioligands targeting VAChT.

Article link：https://www.nature.com/articles/s41594-024-01462-9