9KQA
Cryo-EM structure of human VMAT2 in complex with Tetrabenazine
Summary for 9KQA
| Entry DOI | 10.2210/pdb9kqa/pdb |
| EMDB information | 62498 |
| Descriptor | Soluble cytochrome b562,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 | transporter, vmat2, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 69444.49 |
| Authors | |
| Primary citation | Wei, F.,Liu, H.,Zhang, W.,Wang, J.,Zhang, Y. Drug inhibition and substrate transport mechanisms of human VMAT2. Nat Commun, 16:323-323, 2025 Cited by PubMed Abstract: Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson's disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders. PubMed: 39747030DOI: 10.1038/s41467-024-55361-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.28 Å) |
Structure validation
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