Recognition of anesthetic barbiturates by a protein binding site: a high resolution structural analysis.

PloS One
Simon OakleyPatrick J Loll

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 t...Continue Reading

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Citations

Sep 26, 2013·Journal of Biomolecular Structure & Dynamics·Longhe XuRenyu Liu
Aug 16, 2016·Nature Chemical Biology·Kei YamauraItaru Hamachi
Dec 18, 2016·The Journal of Biological Chemistry·Zaineb FouratiMarc Delarue
Apr 28, 2021·ACS Chemical Neuroscience·Thomas T JosephGrace Brannigan

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