Zhou Zheng, Zhen Juan, Karpowich Nathan K, Law Christopher J, Reith Maarten E A, Wang Da-Neng
Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
Nat Struct Mol Biol. 2009 Jun;16(6):652-7. doi: 10.1038/nsmb.1602. Epub 2009 May 10.
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.
舍曲林和氟西汀是选择性5-羟色胺再摄取抑制剂（SSRI），被广泛用于治疗抑郁症。它们通过抑制突触前质膜5-羟色胺转运体（SERT）发挥作用。所有SSRI在特定位置都含有卤素原子，这些卤素原子是药物对SERT特异性的关键决定因素。然而，对于SERT蛋白，其对SSRI特异性的结构基础仍知之甚少。在此我们报道了细菌SERT同源物亮氨酸转运蛋白（LeuT）与舍曲林、R-氟西汀或S-氟西汀结合的晶体结构。SSRI的卤素都与LeuT内完全相同的口袋结合。SERT中该卤素结合口袋（HBP）处的突变显著降低了转运体对SSRI的亲和力，但对三环类抗抑郁药的亲和力未产生影响。相反，当去甲肾上腺素和多巴胺转运体中唯一的非保守HBP残基突变为SERT中的残基时，它们对所有三种SSRI的亲和力均一致增加。因此，SERT对SSRI的特异性很大程度上取决于药物卤素与蛋白HBP的相互作用。
