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A locally closed conformation of a bacterial pentameric proton-gated ion channel.

Prevost MS, Sauguet L, Nury H, Van Renterghem C, Huon C, Poitevin F, Baaden M, Delarue M, Corringer PJ
Nat Struct Mol Biol 19 642-9 (2012)
Related entries: 3tls, 3tlt, 3tlu, 3tlv, 3tlw, 3uu3, 3uu5, 3uu6, 3uu8, 3uub

Cited: 94 times
EuropePMC logo PMID: 22580559

Abstract

Pentameric ligand-gated ion channels mediate signal transduction through conformational transitions between closed-pore and open-pore states. To stabilize a closed conformation of GLIC, a bacterial proton-gated homolog from Gloeobacter violaceus whose open structure is known, we separately generated either four cross-links or two single mutations. We found all six mutants to be in the same 'locally closed' conformation using X-ray crystallography, sharing most of the features of the open form but showing a locally closed pore as a result of a concerted bending of all of its M2 helices. The mutants adopt several variant conformations of the M2-M3 loop, and in all cases an interacting lipid that is observed in the open form disappears. A single cross-linked mutant is functional, according to electrophysiology, and the locally closed structure of this mutant indicates that it has an increased flexibility. Further cross-linking, accessibility and molecular dynamics data suggest that the locally closed form is a functionally relevant conformation that occurs during allosteric gating transitions.

Articles - 3uu4 mentioned but not cited (1)

  1. X-Ray Crystallographic Studies for Revealing Binding Sites of General Anesthetics in Pentameric Ligand-Gated Ion Channels. Chen Q, Xu Y, Tang P. Methods Enzymol 603 21-47 (2018)


Reviews citing this publication (21)

  1. Molecular Dynamics Simulation for All. Hollingsworth SA, Dror RO. Neuron 99 1129-1143 (2018)
  2. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Changeux JP, Christopoulos A. Cell 166 1084-1102 (2016)
  3. Emerging Molecular Mechanisms of Signal Transduction in Pentameric Ligand-Gated Ion Channels. Nemecz Á, Prevost MS, Menny A, Corringer PJ. Neuron 90 452-470 (2016)
  4. Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery. Hemmings HC, Riegelhaupt PM, Kelz MB, Solt K, Eckenhoff RG, Orser BA, Goldstein PA. Trends Pharmacol Sci 40 464-481 (2019)
  5. 50 years of allosteric interactions: the twists and turns of the models. Changeux JP. Nat Rev Mol Cell Biol 14 819-829 (2013)
  6. A gating mechanism of pentameric ligand-gated ion channels. Calimet N, Simoes M, Changeux JP, Karplus M, Taly A, Cecchini M. Proc Natl Acad Sci U S A 110 E3987-96 (2013)
  7. Structural insights into Cys-loop receptor function and ligand recognition. Nys M, Kesters D, Ulens C. Biochem Pharmacol 86 1042-1053 (2013)
  8. The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. Cecchini M, Changeux JP. Neuropharmacology 96 137-149 (2015)
  9. Gating of pentameric ligand-gated ion channels: structural insights and ambiguities. daCosta CJ, Baenziger JE. Structure 21 1271-1283 (2013)
  10. The dual-gate model for pentameric ligand-gated ion channels activation and desensitization. Gielen M, Corringer PJ. J Physiol 596 1873-1902 (2018)
  11. Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics. Howard RJ, Trudell JR, Harris RA. Pharmacol Rev 66 396-412 (2014)
  12. Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors. Forman SA, Chiara DC, Miller KW. Neuropharmacology 96 169-177 (2015)
  13. Crystallographic studies of pharmacological sites in pentameric ligand-gated ion channels. Sauguet L, Shahsavar A, Delarue M. Biochim Biophys Acta 1850 511-523 (2015)
  14. The nicotinic acetylcholine receptor: a typical 'allosteric machine'. Changeux JP. Philos Trans R Soc Lond B Biol Sci 373 20170174 (2018)
  15. Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors. Burgos CF, Yévenes GE, Aguayo LG. Mol Pharmacol 90 318-325 (2016)
  16. The energy and work of a ligand-gated ion channel. Auerbach A. J Mol Biol 425 1461-1475 (2013)
  17. Allosteric modulation as a unifying mechanism for receptor function and regulation. Changeux JP, Christopoulos A. Diabetes Obes Metab 19 Suppl 1 4-21 (2017)
  18. Allosteric regulation of pentameric ligand-gated ion channels: an emerging mechanistic perspective. Taly A, Hénin J, Changeux JP, Cecchini M. Channels (Austin) 8 350-360 (2014)
  19. Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses. Burgos CF, Muñoz B, Guzman L, Aguayo LG. Pharmacol Res 101 18-29 (2015)
  20. The concept of allosteric interaction and its consequences for the chemistry of the brain. Changeux JP. J Biol Chem 288 26969-26986 (2013)
  21. Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels. Cheng WWL, Arcario MJ, Petroff JT. Front Physiol 12 798102 (2021)

Articles citing this publication (72)



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