Recent atomic-scale structures of pentameric ligand-gated ion channels (pLGICs) from lower organisms provide unique opportunities to characterize the structural basis of allosteric modulation. We have applied mutagenesis and labeling data to structures such as that of the Gloeobacter violaceus ligand-gated ion channel (GLIC) to predict general cavities and specific residues involved in modulation by alcohols and other anesthetics. We have then taken an iterative functional and computational approach, testing wild-type and mutant channel function in Xenopus laevis oocytes, simulating the impact of interesting mutants with molecular dynamics, and using the resulting models to predict further sites of modification. This approach has facilitated refinement of modulation hypotheses for pLGICs from humans as well as model organisms, and has demonstrated the value of integrating functional and computational methods in elucidating complex structural phenomena.

Combined functional-computational approach to characterize sites of anesthetic modulation of ligand-gated ion channels

243rd National Meeting (2012)

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