Differentiating ligand and inhibitor interactions of a single antiporter |
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Authors: | Kedrov Alexej Ziegler Christine Muller Daniel J |
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Affiliation: | BIOTEC, University of Technology, 01307 Dresden, Germany. |
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Abstract: | Regulatory mechanisms of ion and solute transporters are in focus of biomedical and biochemical studies and build a key for disease therapies. Inhibition of sodium/proton exchangers efficiently prevents ischemic heart disease and reperfusion development in humans, but molecular mechanisms behind are not clear. Using single-molecule force spectroscopy we observe the binding of the inhibitor 2-aminoperimidine (AP) to sodium/proton antiporters NhaA from Escherichia coli. Deactivating interactions were significantly suppressed at enhanced sodium concentrations of 200 mM as well as in the pH-locked inactive conformation of NhaA. New molecular interactions were quantified and localized within the protein occurring upon a competitive inhibitor binding. The inhibitor, which was targeted and bound to the ligand-binding pocket, altered interactions established at alpha-helix IX. These molecular mechanisms deactivating the antiporter were different to those established upon ligand binding and activation of NhaA. |
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Keywords: | AP, 2-aminoperimidine SMFS, single-molecule force spectroscopy AFM, atomic force microscopy aa, amino acid residues F-D, force-distance |
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