Glycine receptor mechanism elucidated by electron cryo-microscopy

Nature
Juan DuEric Gouaux

Abstract

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain 'wrist' interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors.

References

Sep 1, 1992·Neuron·R J VandenbergP R Schofield
Oct 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·A B Young, S H Snyder
May 13, 1967·Nature·R WermanM H Aprison
Sep 30, 1967·Nature·D R CurtisG A Johnston
Jan 1, 1968·Experimental Brain Research·D R CurtisI H Johnston
Nov 1, 1965·Life Sciences·M H Aprison, R Werman
Apr 5, 1983·European Journal of Biochemistry·D GrahamH Betz
Feb 1, 1995·Trends in Neurosciences·S Rajendra, P R Schofield
Jul 22, 1993·Proceedings. Biological Sciences·K Fatima-Shad, P H Barry
Mar 5, 1996·Proceedings of the National Academy of Sciences of the United States of America·J L GalziJ Changeux
Dec 1, 1996·Journal of Molecular Graphics·O S SmartM S Sansom
Dec 18, 1998·Neuron·J P Changeux, S J Edelstein
Mar 30, 2001·The Journal of Biological Chemistry·Q ShanJ W Lynch
Jul 5, 2001·Cellular and Molecular Life Sciences : CMLS·P Legendre
Jun 5, 2003·Journal of Structural Biology·Joseph A Mindell, Nikolaus Grigorieff
Jun 27, 2003·Nature·Atsuo MiyazawaNigel Unwin
Aug 29, 1957·The Journal of Physiology·B KATZ, S THESLEFF
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Sep 24, 2004·Physiological Reviews·Joseph W Lynch
Feb 11, 2005·Journal of Molecular Biology·Nigel Unwin
Jun 16, 2005·The Journal of General Physiology·Nuriya MukhtasimovaSteven M Sine
Nov 23, 2005·Bioinformatics·Konstantin ArnoldTorsten Schwede
Jul 25, 2006·Journal of Structural Biology·Guang TangSteven J Ludtke
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Jan 26, 2010·Trends in Pharmacological Sciences·Paul S Miller, Trevor G Smart
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Jul 31, 2012·Nature Methods·Sjors H W Scheres, Shaoxia Chen
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
Oct 5, 2012·Proceedings of the National Academy of Sciences of the United States of America·Radovan SpurnyChris Ulens
Mar 13, 2013·The Journal of General Physiology·Prasad Purohit, Anthony Auerbach
Aug 13, 2013·Structure·Corrie J B daCosta, John E Baenziger
Oct 8, 2013·Proceedings of the National Academy of Sciences of the United States of America·Myles H Akabas
Nov 12, 2013·Nature Methods·Alp KucukelbirHemant D Tagare
Dec 20, 2013·Nature Communications·Prasad PurohitAnthony Auerbach
Dec 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ludovic SauguetMarc Delarue

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Citations

Feb 9, 2016·Toxicon : Official Journal of the International Society on Toxinology·Maciej OstrowskiGrazyna Faure
Jan 15, 2016·ACS Chemical Neuroscience·Nina BraunStephan A Pless
Nov 17, 2015·ACS Chemical Neuroscience·Cecilia M BorgheseR Adron Harris
Mar 30, 2016·Structure·Benoist LaurentMarc Baaden
Apr 7, 2016·Biochemical and Biophysical Research Communications·Xiaojun XuYongchang Chang
Apr 6, 2016·Scientific Reports·Akash PandhareMichaela Jansen
Apr 17, 2016·Progress in Lipid Research·Francisco J Barrantes, Jacques Fantini
Nov 18, 2015·Basic & Clinical Pharmacology & Toxicology·Azadeh ShahsavarThomas Balle
May 31, 2016·Cell·Alan MerkSriram Subramaniam
Jun 23, 2016·Frontiers in Molecular Neuroscience·Georg Langlhofer, Carmen Villmann
Jul 6, 2016·Frontiers in Molecular Neuroscience·Roshan PuthenkalamMargot Ernst
Apr 30, 2016·British Journal of Pharmacology·Cesar O LaraGonzalo E Yévenes
May 20, 2016·The Journal of Physiology·Daniel T Baptista-HonTim G Hales
Jul 28, 2016·Journal of Computer-aided Molecular Design·Alexey V Rossokhin, Boris S Zhorov
Aug 6, 2016·Proceedings of the National Academy of Sciences of the United States of America·Nikolaos KouvatsosSocrates J Tzartos
Jul 13, 2016·Molecular Pharmacology·Carlos F BurgosLuis G Aguayo
Aug 28, 2016·Cell·Jean-Pierre Changeux, Arthur Christopoulos
Oct 4, 2016·Biochimica Et Biophysica Acta. Biomembranes·Jennifer NeumannUte A Hellmich
Oct 21, 2016·Nature·Claudio L Morales-PerezRyan E Hibbs
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mieke NysChris Ulens
Nov 9, 2016·Micron : the International Research and Review Journal for Microscopy·Jan RheinbergerXiaodan Li
Dec 20, 2016·Nature Structural & Molecular Biology·Xin HuangJacinthe Gingras
Dec 15, 2016·Journal of Natural Products·Amal M Y MohsenDarius P Zlotos
Oct 5, 2016·Cellular and Molecular Life Sciences : CMLS·Paul Linsdell
Nov 20, 2016·Angewandte Chemie·Felipe Merino, Stefan Raunser
Feb 16, 2017·British Journal of Pharmacology·Jingyi Wang, Jon Lindstrom
Mar 7, 2017·British Journal of Pharmacology·Cecilia Bouzat, Steven M Sine
Mar 16, 2017·ELife·Anaïs MennyPierre-Jean Corringer
Apr 22, 2017·Physical Chemistry Chemical Physics : PCCP·M A MichałowskiJ W Mozrzymas
Mar 8, 2018·Angewandte Chemie·Melanie Trobe, Martin D Burke
Feb 28, 2018·The Journal of Physiology·Marc Gielen, Pierre-Jean Corringer

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