期刊
BIOPHYSICAL JOURNAL
卷 103, 期 5, 页码 878-888出版社
CELL PRESS
DOI: 10.1016/j.bpj.2012.07.044
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资金
- National Institutes of Health [DA023694, DA012408, U54GM087519]
- National Sciences and Engineering Research Council [RGPIN-315019]
- Alberta Innovates Technology Futures New Faculty, Canadian Institute for Health Research New Investigator
- Alberta Innovates Health Solutions Scholar
- Alberta Innovates Health Solutions
- Oak Ridge National Laboratory [BIP-014]
- Ranger at the Texas Advanced Computing Center [TG-MCB090022]
- Canadian Foundation for Innovation
Neurotransmitter:sodium symporter (NSS) proteins are secondary Na+-driven active transporters that terminate neurotransmission by substrate uptake. Despite the availability of high-resolution crystal structures of a bacterial homolog of NSSs-Leucine Transporter (LeuT)-and extensive computational and experimental structure-function studies, unanswered questions remain regarding the transport mechanisms. We used microsecond atomistic molecular-dynamics (MD) simulations and free-energy computations to reveal ion-controlled conformational dynamics of LeuT in relation to binding affinity and selectivity of the more extracellularly positioned Na+ binding site (Na1 site). In the course of MD simulations starting from the occluded state with bound Na+ but in the absence of substrate, we find a spontaneous transition of the extracellular vestibule of LeuT into an outward-open conformation. The outward opening is enhanced by the absence of Na+ and modulated by the protonation state of the Na1-associated Glu-290. Consistently, the Na+ affinity for the Na1 site is inversely correlated with the extent of outward-open character and is lower than in the occluded state with bound substrate; however, the Na1 site retains its selectivity for Na+ over K+ in such conformational transitions. To the best of our knowledge, our findings shed new light on the Na+-driven transport cycle and on the symmetry in structural rearrangements for outward- and inward-open transitions.
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