Structural insights into vesicular monoamine storage and drug interactions

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Biogenic monoamines are crucial neurotransmitters regulated by vesicular monoamine transporters (VMATs).
• VMATs facilitate monoamine storage and neuroprotection via proton antiport, but their structural mechanisms are poorly understood.
• VMATs are key targets for treating neurodegenerative disorders, hypertension, and addiction.

Purpose of the Study:

• To elucidate the structural mechanisms of human VMAT1 in complex with various substrates.
• To provide insights into the transport mechanism and substrate specificity of VMATs.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine eight structures of human VMAT1.
• Structures were obtained for unbound VMAT1 and in complex with monoamines, MPP+, amphetamine, and reserpine.

Main Results:

• Eight cryo-EM structures of human VMAT1 reveal distinct conformations (cytoplasmic-open and lumenal-open).
• Monoamines, neurotoxicants, and drugs bind to a shared pocket with specific polar sites and a versatile shape.
• Reserpine binding induces a cytoplasmic-open state, while other substrates stabilize a lumenal-open state crucial for transport.

Conclusions:

• Structural insights elucidate the mechanism of vesicular monoamine transport and VMAT gating.
• Understanding VMAT structure provides a basis for developing therapeutics for neurological diseases and substance abuse.