A Unitary Anesthetic-Binding Site at High Resolution

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2009-01, Vol.284
Main Authors: Vedula, L., Brannigan, G, Economou, N, Xi, J, Hall, M, Liu, R, Rossi, M, Dailey, W, Grasty, K, et. al
Format: Article
Language:English
Subjects:
08 HYDROGEN
ANESTHETICS
BASIC BIOLOGICAL SCIENCES
BIOLOGY
COMPLEXES
CRYSTAL STRUCTURE
DYNAMICS
EQUILIBRIUM
FLUCTUATIONS
GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
HYDROGEN
INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY
IONS
LIGANDS
MATERIALS SCIENCE
MIRRORS
national synchrotron light source
PROGRAMMING LANGUAGES
PROTEINS
RECEPTORS
RESOLUTION
TARGETS
USES
VAN DER WAALS FORCES
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 GABA{sub A} 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 GABA{sub A} 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.017814