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Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures.
Elife. 2018 07 20; 7E

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.

Authors+Show Affiliations

Departments of Anesthesiology, Weill Cornell Medical College, New York, United States.Departments of Anesthesiology, Weill Cornell Medical College, New York, United States.Departments of Anesthesiology, Weill Cornell Medical College, New York, United States.Departments of Anesthesiology, Weill Cornell Medical College, New York, United States. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United States. Department of Biochemistry, Weill Cornell Medical College, New York, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30028291

Citation

Rheinberger, Jan, et al. "Ligand Discrimination and Gating in Cyclic Nucleotide-gated Ion Channels From Apo and Partial Agonist-bound cryo-EM Structures." ELife, vol. 7, 2018.
Rheinberger J, Gao X, Schmidpeter PA, et al. Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures. Elife. 2018;7.
Rheinberger, J., Gao, X., Schmidpeter, P. A., & Nimigean, C. M. (2018). Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures. ELife, 7. https://doi.org/10.7554/eLife.39775
Rheinberger J, et al. Ligand Discrimination and Gating in Cyclic Nucleotide-gated Ion Channels From Apo and Partial Agonist-bound cryo-EM Structures. Elife. 2018 07 20;7 PubMed PMID: 30028291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures. AU - Rheinberger,Jan, AU - Gao,Xiaolong, AU - Schmidpeter,Philipp Am, AU - Nimigean,Crina M, Y1 - 2018/07/20/ PY - 2018/07/02/received PY - 2018/07/19/accepted PY - 2018/7/22/pubmed PY - 2019/3/13/medline PY - 2018/7/21/entrez KW - E. coli KW - allostery KW - cryo-electron microscopy KW - cyclic nucleotide-gated ion channel KW - lipid nanodisc KW - molecular biophysics KW - partial agonism KW - single-channel recording KW - structural biology JF - eLife JO - Elife VL - 7 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/30028291/Ligand_discrimination_and_gating_in_cyclic_nucleotide-gated_ion_channels_from_apo_and_partial_agonist-bound_cryo-EM_structures L2 - https://doi.org/10.7554/eLife.39775 DB - PRIME DP - Unbound Medicine ER -