Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 432, Issue 17, Pages 4783-4798Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2020.06.012
Keywords
crystallography; molecular dynamics; free energy; binding; polarization
Categories
Funding
- National Institutes of Health (NIH) [R0GM062342]
- National Institute of General Medical Sciences from the National Institutes of Health [P30 GM124165]
- NIHORIP HEI grant [S10OD021527]
- Department of Energy Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- National Science Foundation (NSF) [PRAC-1640888]
- NIH
- Biological Sciences Division of the University of Chicago
- Argonne National Laboratory [1S10OD018495-01]
- China Scholarship Council [201508210097]
- Natural Science Foundation of Liaoning Province [20180550163]
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Barium (Ba2+) is a classic permeant blocker of potassium (K+) channels. The external lock-in effect in barium block experiments, whereby the binding of external K+ impedes the forward translocation of the blocker, provides a powerful avenue to investigate the selectivity of the binding sites along the pore of potassium channels. Barium block experiments show that the external lock-in site is highly selective for K+ over Na+. Wild-type KcsA was crystallized in low K+ conditions, and the crystals were soaked in solutions containing various concentrations of barium. Structural analysis reveals open and closed gate conformations of the KcsA channel. Anomalous diffraction experiments show that Ba2+ primarily binds to the innermost site S4 of the selectivity filter of the open-gate conformation and also the site S2, but no binding is detected with the closedgate conformation. Alchemical free-energy perturbation calculations indicate that the presence of a Ba2+ ion in the selectivity filter boosts the specificity of K+ binding relative to Na+ in the external sites S0-S2. (C) 2020 Elsevier Ltd. All rights reserved.
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