期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11673
关键词
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资金
- Danscatt program of the Danish Council for Independent Research
- EU-FP7 infrastructure program Biostruct-X [860, 5624]
- Danish Council for Independent Research [FTP-11-105010, DFF-4004-00309]
- Lundbeck Foundation
- Danish National Research Foundation
- Boehringer-Ingelheim Fonds fellowship
- Lundbeck Foundation [R126-2012-12576] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC0002082] Funding Source: researchfish
Bacterial members of the neurotransmitter: sodium symporter (NSS) family perform Na+-dependent amino-acid uptake and extrude H+ in return. Previous NSS structures represent intermediates of Na+/substrate binding or intracellular release, but not the inward-to-outward return transition. Here we report crystal structures of Aquifex aeolicus LeuT in an outward-oriented, Na+-and substrate-free state likely to be H+-occluded. We find a remarkable rotation of the conserved Leu25 into the empty substrate-binding pocket and rearrangements of the empty Na+ sites. Mutational studies of the equivalent Leu99 in the human serotonin transporter show a critical role of this residue on the transport rate. Molecular dynamics simulations show that extracellular Na+ is blocked unless Leu25 is rotated out of the substrate-binding pocket. We propose that Leu25 facilitates the inward-to-outward transition by compensating a Na+-and substrate-free state and acts as the gatekeeper for Na+ binding that prevents leak in inward-outward return transitions.
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