Abstract

Although pentameric ligand-gated ion channels (pLGICs) have been found to be the targets of general anesthetics, the mechanism of the effects of anesthetics on pLGICs remains elusive. pLGICs from Gloeobacter violaceus (GLIC) can be inhibited by the anesthetic ketamine. X-ray crystallography has shown that the ketamine binding site is distant from the channel gate of the GLIC. It is still not clear how ketamine controls the function of the GLIC by long-range allosteric regulation. In this work, the functionally crucial residues and allosteric pathway of anesthetic regulation of the GLIC were identified by use of a coarse-grained thermodynamic method developed by our group. In our method, the functionally crucial sites were identified as the residues thermodynamically coupled with binding of ketamine. The results from calculation were highly consistent with experimental data. Our study aids understanding of the mechanism of the anesthetic action of ketamine on the GLIC by long-range allosteric modulation.

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