期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 16, 期 6, 页码 652-U96出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1602
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资金
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [P30EB009998] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R21GM075936] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH083840] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA013261, R01DA019676] Funding Source: NIH RePORTER
- NIBIB NIH HHS [P30 EB009998] Funding Source: Medline
- NIDA NIH HHS [R01 DA013261, R01 DA013261-07A1, R01 DA013261-08, R01 DA019676-01A1, DA019676, R01 DA019676, R01 DA019676-03, R01 DA019676-02, DA013261, R01 DA013261-09] Funding Source: Medline
- NIGMS NIH HHS [R21 GM075936-02S1, R21 GM075936, GM075936, R21 GM075936-01, R21 GM075936-02] Funding Source: Medline
- NIMH NIH HHS [MH083840, R01 MH083840-01, R01 MH083840] Funding Source: Medline
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.
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