3GWV

Leucine transporter LeuT in complex with R-fluoxetine

Summary for 3GWV

• Entry DOI: 10.2210/pdb3gwv/pdb
• Related: 3GWU 3GWW
• Descriptor: Transporter, LEUCINE, SODIUM ION, ... (5 entities in total)
• Functional Keywords: neurotransmitter, transmembrane transport, integral membrane protein, antidepressant, nss, transport protein, symport, transmembrane, transport
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 1
• Total formula weight: 58097.32

Authors

Zhou, Z.,Zhen, J.,Karpowich, N.K.,Law, C.J.,Reith, M.E.A.,Wang, D.N. (deposition date: 2009-04-01, release date: 2009-05-12, Last modification date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)