期刊
MOLECULAR CELL
卷 30, 期 6, 页码 667-677出版社
CELL PRESS
DOI: 10.1016/j.molcel.2008.05.008
关键词
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资金
- NIDA NIH HHS [K05 DA022413, P01 DA012408, DA012408, K05 DA022413-01A1, R01 DA017293-06, DA017293, DA022413, K05 DA022413-02, R01 DA017293, R01 DA017293-05] Funding Source: Medline
Eukaryotic neurotransmitter: sodium symporters (NSSs), targets for antidepressants and psychostimulants, terminate neurotransmission by sodium-driven reuptake. The crystal structure of LeuT(Aa), a prokaryotic NSS homolog, revealed an occluded state in which one leucine and two Na+ ions are bound, but provided limited clues to the molecular mechanism of transport. Using steered molecular dynamics simulations, we explored the substrate translocation pathway of LeuT. We identified a second substrate binding site located in the extracellular vestibule comprised of residues shown recently to participate in binding tricyclic antidepressants. Binding and flux experiments showed that the two binding sites can be occupied simultaneously. The substrate in the secondary site allosterically triggers intracellular release of Na+ and substrate from the primary site, thereby functioning as a symport effector. Because tricyclic antidepressants bind differently to this secondary site, they do not promote substrate release from the primary site and thus act as symport uncouplers and inhibit transport.
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