Journal article
A Unitary Anesthetic Binding Site at High Resolution
The Journal of biological chemistry, v 284(36), pp 24176-24184
04 Sep 2009
PMID: 19605349
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA
A
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
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
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.
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Details
- Title
- A Unitary Anesthetic Binding Site at High Resolution
- Creators
- L. Sangeetha Vedula - From the Departments ofGrace Brannigan - Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 andNicoleta J Economou - theJin Xi - From the Departments ofMichael A Hall - Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 andRenyu Liu - From the Departments ofMatthew J Rossi - theWilliam P Dailey - Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 andKimberly C Grasty - theMichael L Klein - Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 andRoderic G Eckenhoff - From the Departments ofPatrick J Loll - the
- Publication Details
- The Journal of biological chemistry, v 284(36), pp 24176-24184
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- GM51595; GM55876 / National Institutes of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000269380200031
- Scopus ID
- 2-s2.0-69949157213
- Other Identifier
- 991014877657004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology