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TitleTransport and inhibition mechanisms of human VMAT2.
Journal, issue, pagesNature, Vol. 626, Issue 7998, Page 427-434, Year 2024
Publish dateDec 11, 2023
AuthorsDi Wu / Qihao Chen / Zhuoya Yu / Bo Huang / Jun Zhao / Yuhang Wang / Jiawei Su / Feng Zhou / Rui Yan / Na Li / Yan Zhao / Daohua Jiang /
PubMed AbstractVesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of ...Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression. Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease, respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. The structures in three distinct states also reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutic agents.
External linksNature / PubMed:38081299
MethodsEM (single particle)
Resolution2.84 - 3.52 Å
Structure data

36628

8jsw

EMDB-36628, PDB-8jsw:
Human VMAT2 complex with serotonin
Method: EM (single particle) / Resolution: 2.84 Å

36637

8jt9

EMDB-36637, PDB-8jt9:
Human VMAT2 complex with ketanserin
Method: EM (single particle) / Resolution: 2.97 Å

36638

8jta

EMDB-36638, PDB-8jta:
Human VMAT2 complex with tetrabenazine
Method: EM (single particle) / Resolution: 3.36 Å

36640

8jtc

EMDB-36640, PDB-8jtc:
Human VMAT2 complex with reserpine
Method: EM (single particle) / Resolution: 3.52 Å

Chemicals

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM / Serotonin

ChemComp-UYX:
3-[2-[4-(4-fluorophenyl)carbonylpiperidin-1-yl]ethyl]-1~{H}-quinazoline-2,4-dione

ChemComp-YHL:
tetrabenazine

ChemComp-YHR:
reserpine

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / transporterA / transporter1 / transporter2

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