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GABAA receptor signalling mechanisms revealed by structural pharmacology.

<div class='caption-title'>Structure of the α1β3γ2L GABAAR in complex with picrotoxin (PTX).</div>
<div class='caption-title'>Conformational impact of GABA binding to the α1β3γ2L GABAAR.</div>
<div class='caption-title'>Structure of a α1β3γ2L GABAAR closed by the competitive antagonist bicuculline.</div>
Masiulis S, Desai R, Uchański T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR
OpenAccess logo Nature 565 454-459 (2019)
Related entries: 6huj, 6huk, 6huo, 6hup

Cited: 239 times
EuropePMC logo PMID: 30602790

Abstract

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.

Reviews - 6hug mentioned but not cited (3)

  1. Drug discovery in the era of cryo-electron microscopy. Robertson MJ, Meyerowitz JG, Skiniotis G. Trends Biochem Sci 47 124-135 (2022)
  2. Highlighting membrane protein structure and function: A celebration of the Protein Data Bank. Li F, Egea PF, Vecchio AJ, Asial I, Gupta M, Paulino J, Bajaj R, Dickinson MS, Ferguson-Miller S, Monk BC, Stroud RM. J Biol Chem 296 100557 (2021)
  3. Pose Classification Using Three-Dimensional Atomic Structure-Based Neural Networks Applied to Ion Channel-Ligand Docking. Shim H, Kim H, Allen JE, Wulff H. J Chem Inf Model 62 2301-2315 (2022)

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  1. A guide to: generation and design of nanobodies. Muyldermans S. FEBS J 288 2084-2102 (2021)
  2. 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)
  3. Electrophysiology of ionotropic GABA receptors. Sallard E, Letourneur D, Legendre P. Cell Mol Life Sci 78 5341-5370 (2021)
  4. Progress in nicotinic receptor structural biology. Gharpure A, Noviello CM, Hibbs RE. Neuropharmacology 171 108086 (2020)
  5. Direct Structural Insights into GABAA Receptor Pharmacology. Kim JJ, Hibbs RE. Trends Biochem Sci 46 502-517 (2021)
  6. GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors. Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, Golani LK, Cook JM, Witkin JM. Pharmacol Ther 234 108035 (2022)
  7. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience. Lüscher B, Möhler H. F1000Res 8 F1000 Faculty Rev-751 (2019)
  8. Protein Design: From the Aspect of Water Solubility and Stability. Qing R, Hao S, Smorodina E, Jin D, Zalevsky A, Zhang S. Chem Rev 122 14085-14179 (2022)
  9. A half century of γ-aminobutyric acid. Smart TG, Stephenson FA. Brain Neurosci Adv 3 2398212819858249 (2019)
  10. Cryo-EM as a powerful tool for drug discovery. Van Drie JH, Tong L. Bioorg Med Chem Lett 30 127524 (2020)
  11. Nanobody-Based Probes for Subcellular Protein Identification and Visualization. de Beer MA, Giepmans BNG. Front Cell Neurosci 14 573278 (2020)
  12. Molecular and clinical descriptions of patients with GABAA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation. Maillard PY, Baer S, Schaefer É, Desnous B, Villeneuve N, Lépine A, Fabre A, Lacoste C, El Chehadeh S, Piton A, Porter LF, Perriard C, Wardé MA, Spitz MA, Laugel V, Lesca G, Putoux A, Ville D, Mignot C, Héron D, Nabbout R, Barcia G, Rio M, Roubertie A, Meyer P, Paquis-Flucklinger V, Patat O, Lefranc J, Gerard M, Epigen Consortium, de Bellescize J, Villard L, De Saint Martin A, Milh M. Epilepsia 63 2519-2533 (2022)
  13. Regulation of GABAARs by Transmembrane Accessory Proteins. Han W, Shepard RD, Lu W. Trends Neurosci 44 152-165 (2021)
  14. The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets. Vitale RM, Iannotti FA, Amodeo P. Int J Mol Sci 22 4876 (2021)
  15. Looking for Novelty in an "Old" Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology. Castellano D, Shepard RD, Lu W. Front Neurosci 14 616298 (2020)
  16. Allosteric GABAA Receptor Modulators-A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility. Vega Alanis BA, Iorio MT, Silva LL, Bampali K, Ernst M, Schnürch M, Mihovilovic MD. Molecules 25 E999 (2020)
  17. A minireview of hydroamination catalysis: alkene and alkyne substrate selective, metal complex design. Huo J, He G, Chen W, Hu X, Deng Q, Chen D. BMC Chem 13 89 (2019)
  18. Towards the Idea of Molecular Brains. Timsit Y, Grégoire SP. Int J Mol Sci 22 11868 (2021)
  19. Benzodiazepine Modulation of GABAA Receptors: A Mechanistic Perspective. Goldschen-Ohm MP. Biomolecules 12 1784 (2022)
  20. Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy. Janković SM, Dješević M, Janković SV. J Exp Pharmacol 13 235-244 (2021)
  21. Psychotropic Drugs for the Management of Chronic Pain and Itch. Belinskaia DA, Belinskaia MA, Barygin OI, Vanchakova NP, Shestakova NN. Pharmaceuticals (Basel) 12 E99 (2019)
  22. 3D electron diffraction for structure determination of small-molecule nanocrystals: A possible breakthrough for the pharmaceutical industry. Andrusenko I, Gemmi M. Wiley Interdiscip Rev Nanomed Nanobiotechnol 14 e1810 (2022)
  23. Applications and prospects of cryo-EM in drug discovery. Zhu KF, Yuan C, Du YM, Sun KL, Zhang XK, Vogel H, Jia XD, Gao YZ, Zhang QF, Wang DP, Zhang HW. Mil Med Res 10 10 (2023)
  24. Awareness during emergence from anesthesia: Features and future research directions. Cascella M, Bimonte S, Amruthraj NJ. World J Clin Cases 8 245-254 (2020)
  25. GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks. Mazzone GL, Mohammadshirazi A, Aquino JB, Nistri A, Taccola G. Mol Neurobiol 58 3769-3786 (2021)
  26. Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels. Ananchenko A, Hussein TOK, Mody D, Thompson MJ, Baenziger JE. Biomolecules 12 814 (2022)
  27. Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain. Hudson KE, Grau JW. Cells 11 2910 (2022)
  28. Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy. Boleti APA, Cardoso PHO, Frihling BEF, de Moraes LFRN, Nunes EAC, Mukoyama LTH, Nunes EAC, Carvalho CME, Macedo MLR, Migliolo L. Brain Sci 14 71 (2024)
  29. Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold-A Short Review of Most Recent Studies 2013-2022. Kozyra P, Pitucha M. Int J Mol Sci 23 8874 (2022)
  30. Functional Alternatives to Alcohol. Nutt DJ, Tyacke RJ, Spriggs M, Jacoby V, Borthwick AD, Belelli D. Nutrients 14 3761 (2022)
  31. Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design. Zhu Z, Deng Z, Wang Q, Wang Y, Zhang D, Xu R, Guo L, Wen H. Front Pharmacol 13 939555 (2022)
  32. Change the channel: CysLoop receptor antagonists from nature. Tong G, Baker MA, Shenvi RA. Pest Manag Sci 77 3650-3662 (2021)
  33. Clerodane Diterpenes from Casearia corymbosa as Allosteric GABAA Receptor Modulators. Syafni N, Faleschini MT, Garifulina A, Danton O, Gupta MP, Hering S, Hamburger M. J Nat Prod 85 1201-1210 (2022)
  34. Dependence liability of lormetazepam: are all benzodiazepines equal? The case of the new i.v. lormetazepam for anesthetic procedures. Horowski R. J Neural Transm (Vienna) 127 1107-1115 (2020)
  35. Medicinal Chemistry of Drugs with N-Oxide Functionalities. Kobus M, Friedrich T, Zorn E, Burmeister N, Maison W. J Med Chem 67 5168-5184 (2024)
  36. Neurosteroids and their potential as a safer class of general anesthetics. Tateiwa H, Evers AS. J Anesth 38 261-274 (2024)
  37. The modes of action of ion-channel-targeting neurotoxic insecticides: lessons from structural biology. Raisch T, Raunser S. Nat Struct Mol Biol 30 1411-1427 (2023)
  38. An Update on Stiripentol Mechanisms of Action: A Narrative Review. Bacq A, Depaulis A, Castagné V, Le Guern ME, Wirrell EC, Verleye M. Adv Ther 41 1351-1371 (2024)
  39. Looking for a Beam of Light to Heal Chronic Pain. Xu J, Zhang H, Chen D, Xu K, Li Z, Wu H, Geng X, Wei X, Wu J, Cui W, Wei S. J Pain Res 17 1091-1105 (2024)
  40. Nanobodies in the fight against infectious diseases: repurposing nature's tiny weapons. Rizk SS, Moustafa DM, ElBanna SA, Nour El-Din HT, Attia AS. World J Microbiol Biotechnol 40 209 (2024)
  41. Cryo-electron microscopy-based drug design. Cebi E, Lee J, Subramani VK, Bak N, Oh C, Kim KK. Front Mol Biosci 11 1342179 (2024)
  42. Homology Modeling of Transporter Proteins. Sylte I, Gabrielsen M, Kristiansen K. Methods Mol Biol 2627 247-264 (2023)
  43. Investigation of Potential Drug Targets Involved in Inflammation Contributing to Alzheimer's Disease Progression. Sharo C, Zhai T, Huang Z. Pharmaceuticals (Basel) 17 137 (2024)
  44. Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae. Menzikov SA, Zaichenko DM, Moskovtsev AA, Morozov SG, Kubatiev AA. Front Pharmacol 15 1272534 (2024)
  45. Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies. Mohamad FH, Mohamad Jamali MA, Che Has AT. J Mol Neurosci 73 804-817 (2023)
  46. Unraveling the Mechanisms of Cannabidiol's Pharmacological Actions: A Comprehensive Research Overview. Kalsoom I, Shehzadi K, Li HS, Wen HL, Yu MJ. Top Curr Chem (Cham) 382 20 (2024)
  47. VHH Nanobody Versatility against Pentameric Ligand-Gated Ion Channels. Nemecz D, Nowak WA, Nemecz Á. J Med Chem 67 8502-8518 (2024)

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