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  • 1.
    Brömstrup, Torben
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Inst Pasteur, Grp Recepteurs Canaux, France.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Single-site mutation changes the location of the most favored Desflurane binding site in the GLIC ligand-gated ion channel2012In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Article in journal (Other academic)
  • 2. Howard, Rebecca J.
    et al.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Broemstrup, Torben
    Horani, Suzzane
    Lee, Ui S.
    Ondricek, Kathryn E.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Bertaccini, Edward J.
    Trudell, James R.
    Harris, R. Adron
    Combined functional-computational approach to characterize sites of anesthetic modulation of ligand-gated ion channels2012In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Article in journal (Other academic)
  • 3.
    Howard, Rebecca J
    et al.
    University of Texas.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Ondricek, Kathryn E
    University of Texas.
    Corringer, Pierre-Jean
    Institut Pasteur.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Trudell, James R
    Stanford University.
    Harris, R Adron
    University of Texas.
    Structural basis for alcohol modulation of a pentameric ligand-gated ion channel2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 29, p. 12149-54Article in journal (Refereed)
    Abstract [en]

    Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.

  • 4. Howard, Rebecca J.
    et al.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Ondricek, Kathryn E.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Trudell, James R.
    Harris, R. Adron
    Structural Basis For Alcohol Modulation of Pentameric Ligand-Gated Ion Channels2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 411A-411AArticle in journal (Other academic)
  • 5.
    Lindahl, Erik
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Howard, R. J.
    Brömstrup, Torben
    KTH.
    Trudell, J. R.
    Bertaccini, E. J.
    The Molecular Mechanism For The Dual Alcohol Modulation Of Cys-Loop Receptors2012In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 36, p. 74A-74AArticle in journal (Other academic)
  • 6.
    Lindahl, Erik
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Howard, Rebecca J.
    Brömstrup, Torben
    KTH, School of Biotechnology (BIO).
    Trudell, James
    Bertaccini, Edward J.
    The Molecular Mechanism for the Dual Alcohol Modulation of Cys-Loop Receptors2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 112A-112AArticle in journal (Other academic)
  • 7.
    Murail, Samuel
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Broemstrup, Torben
    Howard, Rebecca
    Trudell, James
    Bertaccini, Edward J.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Molecular mechanism of the dual anesthetic modulation effect on Cys-loop receptors2012In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Article in journal (Other academic)
  • 8.
    Murail, Samuel
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Howard, R. J.
    Broemstrup, Torben
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bertaccini, E. J.
    Harris, R. A.
    Trudell, J. R.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Molecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptors2012In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 10, p. e1002710-Article in journal (Refereed)
    Abstract [en]

    Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-μs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14′)A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.

  • 9.
    Murail, Samuel
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Howard, Rebecca J.
    Trudell, James R.
    Bertaccini, Edward
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Tracing the Closing of a Ligand-Gated Ion Channel in Atomic Detail: An Unconstrained Four-Microsecond Simulation of GLIC Leads to a Closed State Remarkably Similar to ELIC2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 113A-114AArticle in journal (Other academic)
  • 10.
    Murail, Samuel
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Wallner, Björn
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Trudell, James R.
    Bertaccini, Edward
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Microsecond Simulations Indicate that Ethanol Binds between Subunits and Could Stabilize an Open-State Model of a Glycine Receptor2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 7, p. 1642-1650Article in journal (Refereed)
    Abstract [en]

    Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, and gamma-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomeric alpha 1 glycine receptor (GlyR alpha 1), modeled on the structure of the Gloeobacter violaceus pentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (similar to 200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors.

  • 11.
    Yoluk, Özge
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Center for Biomembrane Research.
    Simulations of Subunit Interactions in the C. Elegans GluCl Ligand-Gated2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 472A-472AArticle in journal (Other academic)
1 - 11 of 11
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  • apa
  • harvard1
  • ieee
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  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
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  • text
  • asciidoc
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