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Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures.

<div class='caption-title'>Cryo-EM structures of SthK.</div>
<div class='caption-title'>Purification of SthK in lipid nanodiscs.</div>
<div class='caption-title'>Single particle cryo-EM of apo SthK.</div>
Rheinberger J, Gao X, Schmidpeter PA, Nimigean CM
OpenAccess logo Elife 7 (2018)
Related entries: 6cjq, 6cjt

Cited: 29 times
EuropePMC logo PMID: 30028291

Abstract

Cyclic nucleotide-modulated channels have important roles in visual signal transduction and pacemaking. Binding of cyclic nucleotides (cAMP/cGMP) elicits diverse functional responses in different channels within the family despite their high sequence and structure homology. The molecular mechanisms responsible for ligand discrimination and gating are unknown due to lack of correspondence between structural information and functional states. Using single particle cryo-electron microscopy and single-channel recording, we assigned functional states to high-resolution structures of SthK, a prokaryotic cyclic nucleotide-gated channel. The structures for apo, cAMP-bound, and cGMP-bound SthK in lipid nanodiscs, correspond to no, moderate, and low single-channel activity, respectively, consistent with the observation that all structures are in resting, closed states. The similarity between apo and ligand-bound structures indicates that ligand-binding domains are strongly coupled to pore and SthK gates in an allosteric, concerted fashion. The different orientations of cAMP and cGMP in the 'resting' and 'activated' structures suggest a mechanism for ligand discrimination.

Reviews - 6cju mentioned but not cited (1)

  1. Structural basis of properties, mechanisms, and channelopathy of cyclic nucleotide-gated channels. Hu Z, Yang J. Channels (Austin) 17 2273165 (2023)

Articles - 6cju mentioned but not cited (8)

  1. Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures. Rheinberger J, Gao X, Schmidpeter PA, Nimigean CM. Elife 7 e39775 (2018)
  2. Allosteric conformational change of a cyclic nucleotide-gated ion channel revealed by DEER spectroscopy. Evans EGB, Morgan JLW, DiMaio F, Zagotta WN, Stoll S. Proc Natl Acad Sci U S A 117 10839-10847 (2020)
  3. Anionic lipids unlock the gates of select ion channels in the pacemaker family. Schmidpeter PAM, Wu D, Rheinberger J, Riegelhaupt PM, Tang H, Robinson CV, Nimigean CM. Nat Struct Mol Biol 29 1092-1100 (2022)
  4. Functional characterization and optimization of a bacterial cyclic nucleotide-gated channel. Morgan JLW, Evans EGB, Zagotta WN. J Biol Chem 294 7503-7515 (2019)
  5. Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel. Schmidpeter PAM, Rheinberger J, Nimigean CM. Nat Commun 11 6401 (2020)
  6. Correlating ion channel structure and function. Schmidpeter PAM, Nimigean CM. Methods Enzymol 652 3-30 (2021)
  7. Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel. Gao X, Schmidpeter PAM, Berka V, Durham RJ, Fan C, Jayaraman V, Nimigean CM. Nat Commun 13 6919 (2022)
  8. Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Pan Y, Pohjolainen E, Schmidpeter PAM, Vaiana AC, Nimigean CM, Grubmüller H, Scheuring S. Nat Struct Mol Biol 30 512-520 (2023)


Reviews citing this publication (5)

  1. Advances in high-speed atomic force microscopy (HS-AFM) reveal dynamics of transmembrane channels and transporters. Heath GR, Scheuring S. Curr Opin Struct Biol 57 93-102 (2019)
  2. Direct Structural Insights into GABAA Receptor Pharmacology. Kim JJ, Hibbs RE. Trends Biochem Sci 46 502-517 (2021)
  3. Frontiers in Cryo Electron Microscopy of Complex Macromolecular Assemblies. Ognjenović J, Grisshammer R, Subramaniam S. Annu Rev Biomed Eng 21 395-415 (2019)
  4. Lipid Membrane Mimetics in Functional and Structural Studies of Integral Membrane Proteins. Majeed S, Ahmad AB, Sehar U, Georgieva ER. Membranes (Basel) 11 685 (2021)
  5. hERG Function in Light of Structure. Robertson GA, Morais-Cabral JH. Biophys J 118 790-797 (2020)

Articles citing this publication (15)

  1. Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance. Enkavi G, Javanainen M, Kulig W, Róg T, Vattulainen I. Chem Rev 119 5607-5774 (2019)
  2. New tools in MolProbity validation: CaBLAM for CryoEM backbone, UnDowser to rethink "waters," and NGL Viewer to recapture online 3D graphics. Prisant MG, Williams CJ, Chen VB, Richardson JS, Richardson DC. Protein Sci 29 315-329 (2020)
  3. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. Falzone ME, Rheinberger J, Lee BC, Peyear T, Sasset L, Raczkowski AM, Eng ET, Di Lorenzo A, Andersen OS, Nimigean CM, Accardi A. Elife 8 e43229 (2019)
  4. An iris diaphragm mechanism to gate a cyclic nucleotide-gated ion channel. Marchesi A, Gao X, Adaixo R, Rheinberger J, Stahlberg H, Nimigean C, Scheuring S. Nat Commun 9 3978 (2018)
  5. Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel. Zheng X, Fu Z, Su D, Zhang Y, Li M, Pan Y, Li H, Li S, Grassucci RA, Ren Z, Hu Z, Li X, Zhou M, Li G, Frank J, Yang J. Nat Struct Mol Biol 27 625-634 (2020)
  6. Structural mechanisms of gating and selectivity of human rod CNGA1 channel. Xue J, Han Y, Zeng W, Wang Y, Jiang Y. Neuron 109 1302-1313.e4 (2021)
  7. Bipolar switching by HCN voltage sensor underlies hyperpolarization activation. Cowgill J, Klenchin VA, Alvarez-Baron C, Tewari D, Blair A, Chanda B. Proc Natl Acad Sci U S A 116 670-678 (2019)
  8. VESPER: global and local cryo-EM map alignment using local density vectors. Han X, Terashi G, Christoffer C, Chen S, Kihara D. Nat Commun 12 2090 (2021)
  9. Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel. Patel VR, Salinas AM, Qi D, Gupta S, Sidote DJ, Goldschen-Ohm MP. Nat Commun 12 6459 (2021)
  10. Fluorescence Titrations to Determine the Binding Affinity of Cyclic Nucleotides to SthK Ion Channels. Schmidpeter PAM, Nimigean CM. Bio Protoc 8 e3041 (2018)
  11. Reconstitution of Membrane Proteins into Platforms Suitable for Biophysical and Structural Analyses. Schmidpeter PAM, Sukomon N, Nimigean CM. Methods Mol Biol 2127 191-205 (2020)
  12. Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel. Hu Z, Zheng X, Yang J. Nat Commun 14 4284 (2023)
  13. Native Function of the Bacterial Ion Channel SthK in a Sparsely Tethered Lipid Bilayer Membrane Architecture. Andersson J, Kleinheinz D, Ramach U, Kiesenhofer N, Ashenden A, Valtiner M, Holt S, Koeper I, Schmidpeter PAM, Knoll W. J Phys Chem B 127 3641-3650 (2023)
  14. Congress A mighty stream of membrane proteins. Miller C. Nat Struct Mol Biol 25 751-753 (2018)
  15. Structures of a sperm-specific solute carrier gated by voltage and cAMP. Kalienkova V, Peter MF, Rheinberger J, Paulino C. Nature 623 202-209 (2023)


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