8THR

Structure of the human vesicular monoamine transporter 2 (VMAT2) bound to tetrabenazine in an occluded conformation

Summary for 8THR

• Entry DOI: 10.2210/pdb8thr/pdb
• EMDB information: 41269
• Descriptor: fluorescent protein mVenus,Synaptic vesicular amine transporter,GFP nano body,Synaptic vesicular amine transporter,Synaptic vesicular amine transporter, (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (2 entities in total)
• Functional Keywords: monoamine, neurotransmitter, synaptic vesicles, major facilitator superfamily, slc18, transport protein
• Biological source: Aequorea victoria; More
• Total number of polymer chains: 1
• Total formula weight: 94168.35

Authors

Dalton, M.P.,Coleman, J.A. (deposition date: 2023-07-17, release date: 2023-10-25, Last modification date: 2024-05-08)

Primary citation

Dalton, M.P.,Cheng, M.H.,Bahar, I.,Coleman, J.A.
Structural mechanisms for VMAT2 inhibition by tetrabenazine.
Elife, 12:-, 2024

PubMed Abstract: The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

PubMed: 38517752
DOI: 10.7554/eLife.91973

Experimental method

ELECTRON MICROSCOPY (3.12 Å)