ArticleBiophysical journal2008
Four-alpha-helix bundle with designed anesthetic binding pockets. Part II: halothane effects on structure and dynamics.
Article in Biophysical journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 38 citations in OpenAlex.
- Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.ACS chemical neuroscience · 2023Article
- Solution NMR Studies of Anesthetic Interactions with Ion Channels.Methods in enzymology · 2018Article
- Atomistic insights into human Cys-loop receptors by solution NMR.Biochimica et biophysica acta · 2015Article
- NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites.Biochimica et biophysica acta · 2014Article
- Theoretical studies of the interaction between enflurane and water.Journal of molecular modeling · 2013Article
- NMR resolved multiple anesthetic binding sites in the TM domains of the α4β2 nAChR.Biochimica et biophysica acta · 2013Article
- General anesthetics predicted to block the GLIC pore with micromolar affinity.PLoS computational biology · 2012Article
- Isoflurane selectively inhibits distal mitochondrial complex I in Caenorhabditis elegans.Anesthesia and analgesia · 2011Article
- Binding of small molecules to cavity forming mutants of a de novo designed protein.Protein science : a publication of the Protein Society · 2011Article
- Anesthetic binding in a pentameric ligand-gated ion channel: GLIC.Biophysical journal · 2010Article
- New insights into the molecular mechanisms of general anaesthetics.British journal of pharmacology · 2010Review
- Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.The journal of physical chemistry. B · 2010Article
- General anesthetic binding to neuronal alpha4beta2 nicotinic acetylcholine receptor and its effects on global dynamics.The journal of physical chemistry. B · 2009Article
- Mechanism of interaction between the general anesthetic halothane and a model ion channel protein, I: Structural investigations via X-ray reflectivity from Langmuir monolayers.Biophysical journal · 2009Article
- Mechanism of interaction between the general anesthetic halothane and a model ion channel protein, III: Molecular dynamics simulation incorporating a cyanophenylalanine spectroscopic probe.Biophysical journal · 2009Article
- Anesthetic modulation of protein dynamics: insight from an NMR study.The journal of physical chemistry. B · 2008Article
- Four-alpha-helix bundle with designed anesthetic binding pockets. Part I: structural and dynamical analyses.Biophysical journal · 2008Article
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8 authors at 2 institutions in 1 country.
Funding
Abstract
As a model of the protein targets for volatile anesthetics, the dimeric four-alpha-helix bundle, (Aalpha(2)-L1M/L38M)(2), was designed to contain a long hydrophobic core, enclosed by four amphipathic alpha-helices, for specific anesthetic binding. The structural and dynamical analyses of (Aalpha(2)-L1M/L38M)(2) in the absence of anesthetics (another study) showed a highly dynamic antiparallel dimer with an asymmetric arrangement of the four helices and a lateral accessing pathway from the aqueous phase to the hydrophobic core. In this study, we determined the high-resolution NMR structure of (Aalpha(2)-L1M/L38M)(2) in the presence of halothane, a clinically used volatile anesthetic. The high-solution NMR structure, with a backbone root mean-square deviation of 1.72 A (2JST), and the NMR binding measurements revealed that the primary halothane binding site is located between two side-chains of W15 from each monomer, different from the initially designed anesthetic binding sites. Hydrophobic interactions with residues A44 and L18 also contribute to stabilizing the bound halothane. Whereas halothane produces minor changes in the monomer structure, the quaternary arrangement of the dimer is shifted by about half a helical turn and twists relative to each other, which leads to the closure of the lateral access pathway to the hydrophobic core. Quantitative dynamics analyses, including Modelfree analysis of the relaxation data and the Carr-Purcell-Meiboom-Gill transverse relaxation dispersion measurements, suggest that the most profound anesthetic effect is the suppression of the conformational exchange both near and remote from the binding site. Our results revealed a novel mechanism of an induced fit between anesthetic molecule and its protein target, with the direct consequence of protein dynamics changing on a global rather than a local scale. This mechanism may be universal to anesthetic action on neuronal proteins.
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