Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures.
Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures.
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DOI：
10.1038/nsmb.1602
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发表时间：
2009-06
影响因子：
16.8
通讯作者：
中科院分区：
文献类型：
--
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Sertraline and fluoxetine are selective serotonin reuptake inhibitors (SSRIs) widely-prescribed to treat depression. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter (SERT). All SSRIs possess at specific positions halogen atoms, 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 dramatically reduces the transporter's affinity for SSRIs but not for tricyclic antidepressants. Conversely, when the only non-conserved 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 halogen-binding pocket.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.6
作者：
Law, Christopher J.;Almqvist, Jonas;Wang, Da-Neng
通讯作者：
Wang, Da-Neng
影响因子：
4.8
作者：
Androutsellis-Theotokis, A;Goldberg, NR;Rudnick, G
通讯作者：
Rudnick, G
影响因子：
7.3
作者：
Iversen, L
通讯作者：
Iversen, L
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL