3GWU

Leucine transporter LeuT in complex with sertraline

3GWU の概要

• エントリーDOI: 10.2210/pdb3gwu/pdb
• 関連するPDBエントリー: 3GWV 3GWW
• 分子名称: Transporter, LEUCINE, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: neurotransmitter, transmembrane transport, integral membrane protein, antidepressant, nss, transport protein, symport, transmembrane, transport
• 由来する生物種: Aquifex aeolicus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58094.22

構造登録者

Zhou, Z.,Zhen, J.,Karpowich, N.K.,Law, C.J.,Reith, M.E.A.,Wang, D.N. (登録日: 2009-04-01, 公開日: 2009-05-12, 最終更新日: 2023-09-06)

主引用文献

Zhou, Z.,Zhen, J.,Karpowich, N.K.,Law, C.J.,Reith, M.E.,Wang, D.N.
Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures.
Nat.Struct.Mol.Biol., 16:652-657, 2009

PubMed Abstract: Sertraline and fluoxetine are selective serotonin re-uptake inhibitors (SSRIs) that are widely prescribed to treat depression. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter (SERT). All SSRIs possess halogen atoms at specific positions, which are key determinants for the drugs' specificity for SERT. For the SERT protein, however, the structural basis of its specificity for SSRIs is poorly understood. Here we report the crystal structures of LeuT, a bacterial SERT homolog, in complex with sertraline, R-fluoxetine or S-fluoxetine. The SSRI halogens all bind to exactly the same pocket within LeuT. Mutation at this halogen-binding pocket (HBP) in SERT markedly reduces the transporter's affinity for SSRIs but not for tricyclic antidepressants. Conversely, when the only nonconserved HBP residue in both norepinephrine and dopamine transporters is mutated into that found in SERT, their affinities for all the three SSRIs increase uniformly. Thus, the specificity of SERT for SSRIs is dependent largely on interaction of the drug halogens with the protein's HBP.

PubMed: 19430461
DOI: 10.1038/nsmb.1602

実験手法

X-RAY DIFFRACTION (2.14 Å)