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Structure paper

TitleStructural insights into vesicular monoamine storage and drug interactions.
Journal, issue, pagesNature, Year 2024
Publish dateMar 18, 2024
AuthorsJin Ye / Huaping Chen / Kaituo Wang / Yi Wang / Aaron Ammerman / Samjhana Awasthi / Jinbin Xu / Bin Liu / Weikai Li /
PubMed AbstractBiogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled ...Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.
External linksNature / PubMed:38499039
MethodsEM (single particle)
Resolution3.3 - 3.7 Å
Structure data

41235

8tgg

EMDB-41235, PDB-8tgg:
VMAT1 dimer with MPP+ and reserpine
Method: EM (single particle) / Resolution: 3.6 Å

41236

8tgh

EMDB-41236, PDB-8tgh:
VMAT1 dimer with amphetamine and reserpine
Method: EM (single particle) / Resolution: 3.5 Å

41237

8tgi

EMDB-41237, PDB-8tgi:
VMAT1 dimer with dopamine and reserpine
Method: EM (single particle) / Resolution: 3.4 Å

41238

8tgj

EMDB-41238, PDB-8tgj:
VMAT1 dimer in unbound form and with reserpine
Method: EM (single particle) / Resolution: 3.5 Å

41239

8tgk

EMDB-41239, PDB-8tgk:
VMAT1 dimer with histamine and reserpine
Method: EM (single particle) / Resolution: 3.7 Å

41240

8tgl

EMDB-41240, PDB-8tgl:
VMAT1 dimer with norepinephrine and reserpine
Method: EM (single particle) / Resolution: 3.4 Å

41241

8tgm

EMDB-41241, PDB-8tgm:
VMAT1 dimer with reserpine
Method: EM (single particle) / Resolution: 3.5 Å

41242

8tgn

EMDB-41242, PDB-8tgn:
VMAT1 dimer with serotonin and reserpine
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-WRF:
1-methyl-4-phenylpyridin-1-ium

ChemComp-YHR:
reserpine

ChemComp-1WE:
(2S)-1-phenylpropan-2-amine / Dextroamphetamine

ChemComp-LDP:
L-DOPAMINE / medication*YM / Dopamine (medication)

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*YM / Histamine

ChemComp-LNR:
L-NOREPINEPHRINE / neurotransmitter, hormone*YM / Norepinephrine

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM / Serotonin

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / VMAT / SLC18 / vascular monoamine transporter / monoamines / neurotransmitters / MPP+ / amphetamine / dopamine / reserpine / histamine / norepinephrine / serotonin

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