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TitleTransport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.
Journal, issue, pagesCell Res, Vol. 34, Issue 1, Page 47-57, Year 2024
Publish dateJan 2, 2024
AuthorsYuwei Wang / Pei Zhang / Yulin Chao / Zhini Zhu / Chuanhui Yang / Zixuan Zhou / Yaohui Li / Yonghui Long / Yuehua Liu / Dianfan Li / Sheng Wang / Qianhui Qu /
PubMed AbstractMonoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 ...Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.
External linksCell Res / PubMed:38163846 / PubMed Central
MethodsEM (single particle)
Resolution3.37 - 3.74 Å
Structure data

37621

8wlj

EMDB-37621, PDB-8wlj:
Cryo-EM structure of human apo VMAT2 with nanobody in an outward-facing conformation
Method: EM (single particle) / Resolution: 3.6 Å

37622

8wlk

EMDB-37622, PDB-8wlk:
Cryo-EM structure of human VMAT2 in presence of Tetrabenazine, determined in an outward-facing conformation
Method: EM (single particle) / Resolution: 3.37 Å

37623

8wll

EMDB-37623, PDB-8wll:
Cryo-EM structure of human VMAT2 Y422C, in the presence of reserpine, determined in an inward-facing conformation
Method: EM (single particle) / Resolution: 3.74 Å

37624

8wlm

EMDB-37624, PDB-8wlm:
Cryo-EM structure of human VMAT2 in presence of 5-HT, determined in an outward-facing conformation
Method: EM (single particle) / Resolution: 3.57 Å

Chemicals

ChemComp-EBZ:
(3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one

ChemComp-YHR:
reserpine

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM

Source
  • homo sapiens (human)
  • vicugna pacos (alpaca)
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / Human VMAT2 / outward-facing conformation / TRANSPORT PROTEIN / TRANSPORT PROTEIN-IMMUNE SYSTEM complex / Tetrabenazine / Human VMAT2 Y422C / reserpine / Inward-facing conformation / 5-HT

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