Journal
BIOPHYSICAL JOURNAL
Volume 108, Issue 6, Pages 1390-1399Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2015.02.010
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Funding
- Danish Council for Independent Research/Natural Sciences
- Danish Council for Independent Research/Technology and Production Sciences
- Danish National Research Foundation [DNRF59]
- Danish Center for Scientific Computing
- Lundbeck Foundation [R126-2012-12453] Funding Source: researchfish
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The leucine transporter (LeuT) is a bacterial homolog of the human monoamine transporters, which are important pharmaceutical targets. There are no high-resolution structures of the human transporters available; however, LeuT has been crystallized in several different conformational states. Recently, an inward-facing conformation of LeuT was solved revealing an unexpectedly large movement of transmembrane helix 1a (TM1a). We have performed molecular dynamics simulations of the mutated and wild-type transporter, with and without the cocrystallized Fab antibody fragment, to investigate the properties of this inward-facing conformation in relation to transport by LeuT within the membrane environment. In all of the simulations, local conformational changes with respect to the crystal structure are consistently observed, especially in TM1a. Umbrella sampling revealed a soft potential for TM1a tilting. Furthermore, simulations of inward-facing LeuT with Na+ ions and substrate bound suggest that one of the Na+ ion binding sites is fully disrupted. Release of alanine and the second Na+ ion is also observed, giving insight into the final stage of the translocation process in atomistic detail.
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