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TitleBinding mechanism and antagonism of the vesicular acetylcholine transporter VAChT.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 5, Page 818-827, Year 2025
Publish dateJan 13, 2025
AuthorsQiao Ma / Kunpeng Ma / Yanli Dong / Yufei Meng / Jun Zhao / Renjie Li / Qinru Bai / Di Wu / Daohua Jiang / Jianyuan Sun / Yan Zhao /
PubMed AbstractThe vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. ...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.
External linksNat Struct Mol Biol / PubMed:39806024
MethodsEM (single particle)
Resolution2.7 - 3.4 Å
Structure data

EMDB-38651, PDB-8xtw:
Structure of human VAChT in complex with acetylcholine
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-38652, PDB-8xtx:
Structure of human VAChT in an apo conformation
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-38653, PDB-8xty:
Structure of human VAChT in complex with vesamicol
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM

PDB-1lwl:
Crystal Structure of Cytochrome P450-cam with a Fluorescent Probe D-8-Ad (Adamantane-1-carboxylic acid-5-dimethylamino-naphthalene-1-sulfonylamino-octyl-amide)

Source
  • homo sapiens (human)
  • aequorea victoria (jellyfish)
KeywordsTRANSPORT PROTEIN / Transporter / Membrane protein / TRANSPORT PROTEIN/INHIBITOR / TRANSPORT PROTEIN-INHIBITOR complex

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