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  • 1.
    Brömstrup, Torben
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Howard, Rebecca J.
    Trudell, James R.
    Harris, R. Adron
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites2013In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, no 8, p. 1307-1316Article in journal (Refereed)
    Abstract [en]

    Pentameric ligand-gated ion channels (pLGICs) are similar in structure but either inhibited or potentiated by alcohols and anesthetics. This dual modulation has previously not been understood, but the determination of X-ray structures of prokaryotic GLIC provides an ideal model system. Here, we show that a single-site mutation at the F14' site in the GLIC transmembrane domain turns desflurane and chloroform from inhibitors to potentiators, and that this is explained by competing allosteric sites. The F14'A mutation opens an intersubunit site lined by N239 (15'), 1240 (16'), and Y263. Free energy calculations confirm this site is the preferred binding location for desflurane and chloroform in GLIC F14'A. In contrast, both anesthetics prefer an intrasubunit site in wild-type GLIC. Modulation is therefore the net effect of competitive binding between the intersubunit potentiating site and an intrasubunit inhibitory site. This provides direct evidence for a dual-site model of allosteric regulation of pLGICs.

  • 2.
    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)
  • 3. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Borghese, Cecilia M.
    Cullins, Madeline A.
    Brömstrup, Torben
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Ui S.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Carlsson, Jens
    Harris, R. Adron
    Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channelss2013In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 84, no 5, p. 670-678Article in journal (Refereed)
    Abstract [en]

    GABA(A) receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABA(A) receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABA(A) receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABA(A) receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABA(A), and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor's conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABA(A) receptor ligands.

  • 4. Howard, Rebecca J.
    et al.
    Sauguet, Ludovic
    Brömstrup, Torben
    Swedish e-Science Resarch Centre.
    Murail, Samuel
    Lee, Ui S.
    Horani, Suzzane
    Trudell, James R.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Delarue, Marc
    Harris, R. Adron
    Alcohol and Anesthetic Binding to Pentameric Ligand-Gated Ion Channels Revealed in a Prokaryotic Model System2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 635A-636AArticle in journal (Other academic)
  • 5. Laurent, Benoist
    et al.
    Murail, Samuel
    Brömstrup, Torben
    KTH.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Baaden, Marc
    Study of the Interaction between General Anesthetics and a Bacterial Homologue to the Human Nicotinic Receptor2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 623A-623AArticle in journal (Other academic)
  • 6.
    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)
  • 7.
    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)
  • 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.
    Yoluk, Özge
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Brömstrup, Torben
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Bertaccini, Edward J.
    Trudell, James R.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Stabilization of the GluCl Ligand-Gated Ion Channel in the Presence and Absence of Ivermectin2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, no 3, p. 640-647Article in journal (Refereed)
    Abstract [en]

    Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABA(A)R or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 angstrom closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 angstrom, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior.

1 - 9 of 9
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