A unitary anesthetic binding site at high resolution

L. Sangeetha Vedula, Grace Brannigan, Nicoleta J. Economou, Jin Xi, Michael A. Hall, Renyu Liu, Matthew J. Rossi, William P. Dailey, Kimberly C. Grasty, Michael L. Klein, Roderic G. Eckenhoff, Patrick J. Loll

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABAA receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABAA receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show that apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABAA receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.

Original languageEnglish (US)
Pages (from-to)24176-24184
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number36
DOIs
StatePublished - Sep 4 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A unitary anesthetic binding site at high resolution'. Together they form a unique fingerprint.

  • Cite this

    Vedula, L. S., Brannigan, G., Economou, N. J., Xi, J., Hall, M. A., Liu, R., Rossi, M. J., Dailey, W. P., Grasty, K. C., Klein, M. L., Eckenhoff, R. G., & Loll, P. J. (2009). A unitary anesthetic binding site at high resolution. Journal of Biological Chemistry, 284(36), 24176-24184. https://doi.org/10.1074/jbc.M109.017814