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Neurotransmitter recognition by human vesicular monoamine transporter 2.
Im, Dohyun; Jormakka, Mika; Juge, Narinobu; Kishikawa, Jun-Ichi; Kato, Takayuki; Sugita, Yukihiko; Noda, Takeshi; Uemura, Tomoko; Shiimura, Yuki; Miyaji, Takaaki; Asada, Hidetsugu; Iwata, So.
Afiliação
  • Im D; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. im.dohyun.3s@kyoto-u.ac.jp.
  • Jormakka M; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Juge N; Department of Genomics and Proteomics, Advanced Science Research Center, Okayama University, Okayama, Japan.
  • Kishikawa JI; Department of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Kato T; Department of Applied Biology, Kyoto Institute of Technology, Kyoto, Japan.
  • Sugita Y; Institute for Protein Research, Osaka University, Suita, Japan.
  • Noda T; Institute for Protein Research, Osaka University, Suita, Japan.
  • Uemura T; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
  • Shiimura Y; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • Miyaji T; Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan.
  • Asada H; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
  • Iwata S; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Nat Commun ; 15(1): 7661, 2024 Sep 16.
Article em En | MEDLINE | ID: mdl-39284862
ABSTRACT
Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tetrabenazina / Dopamina / Neurotransmissores / Microscopia Crioeletrônica / Proteínas Vesiculares de Transporte de Monoamina Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tetrabenazina / Dopamina / Neurotransmissores / Microscopia Crioeletrônica / Proteínas Vesiculares de Transporte de Monoamina Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Reino Unido