Journal article
Recognition of anesthetic barbiturates by a protein binding site: a high resolution structural analysis
PloS one, Vol.7(2), pp.e32070-e32070
2012
PMCID: PMC3281113
PMID: 22359658
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Barbiturates potentiate GABA actions at the GABA(A) receptor and act as central nervous system depressants that can induce effects ranging from sedation to general anesthesia. No structural information has been available about how barbiturates are recognized by their protein targets. For this reason, we tested whether these drugs were able to bind specifically to horse spleen apoferritin, a model protein that has previously been shown to bind many anesthetic agents with affinities that are closely correlated with anesthetic potency. Thiopental, pentobarbital, and phenobarbital were all found to bind to apoferritin with affinities ranging from 10-500 µM, approximately matching the concentrations required to produce anesthetic and GABAergic responses. X-ray crystal structures were determined for the complexes of apoferritin with thiopental and pentobarbital at resolutions of 1.9 and 2.0 Å, respectively. These structures reveal that the barbiturates bind to a cavity in the apoferritin shell that also binds haloalkanes, halogenated ethers, and propofol. Unlike these other general anesthetics, however, which rely entirely upon van der Waals interactions and the hydrophobic effect for recognition, the barbiturates are recognized in the apoferritin site using a mixture of both polar and nonpolar interactions. These results suggest that any protein binding site that is able to recognize and respond to the chemically and structurally diverse set of compounds used as general anesthetics is likely to include a versatile mixture of both polar and hydrophobic elements.
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Details
- Title
- Recognition of anesthetic barbiturates by a protein binding site: a high resolution structural analysis
- Creators
- Simon Oakley - Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaL Sangeetha VedulaWeiming BuQing Cheng MengJin XiRenyu LiuRoderic G EckenhoffPatrick J Loll
- Publication Details
- PloS one, Vol.7(2), pp.e32070-e32070
- Publisher
- Public LIbrary of Science (PLOS); United States
- Grant note
- P01 GM055876 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Identifiers
- 991014878549304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology