Journal
SCIENCE
Volume 322, Issue 5908, Pages 1655-1661Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1166777
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Funding
- NIH/National Institute of Neurological Disorders and Stroke National Research Service Award
- NIH/National Institute of Mental Health K99/R00 Pathway to Independence Award
- NIH Multidisciplinary Training in Neuroendocrinology
- NIH
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Secondary transporters are workhorses of cellular membranes, catalyzing the movement of small molecules and ions across the bilayer and coupling substrate passage to ion gradients. However, the conformational changes that accompany substrate transport, the mechanism by which a substrate moves through the transporter, and principles of competitive inhibition remain unclear. We used crystallographic and functional studies on the leucine transporter ( LeuT), a model for neurotransmitter sodium symporters, to show that various amino acid substrates induce the same occluded conformational state and that a competitive inhibitor, tryptophan ( Trp), traps LeuT in an open- to- out conformation. In the Trp complex, the extracellular gate residues arginine 30 and aspartic acid 404 define a second weak binding site for substrates or inhibitors as they permeate from the extracellular solution to the primary substrate site, which demonstrates how residues that participate in gating also mediate permeation.
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