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Proc Natl Acad Sci U S A
2015 Jul 07;11227:E3619-28. doi: 10.1073/pnas.1503334112.
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A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels.
Napolitano LM
,
Bisha I
,
De March M
,
Marchesi A
,
Arcangeletti M
,
Demitri N
,
Mazzolini M
,
Rodriguez A
,
Magistrato A
,
Onesti S
,
Laio A
,
Torre V
.
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Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K(+) channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na(+), Cs(+), and dimethylammonium (DMA(+)), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels.
Adzhubei,
Polyproline-II helix in proteins: structure and function.
2013, Pubmed
Adzhubei,
Polyproline-II helix in proteins: structure and function.
2013,
Pubmed
Arcangeletti,
Multiple mechanisms underlying rectification in retinal cyclic nucleotide-gated (CNGA1) channels.
2013,
Pubmed
,
Xenbase
Baftizadeh,
Multidimensional view of amyloid fibril nucleation in atomistic detail.
2012,
Pubmed
Banke,
Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation.
2010,
Pubmed
Bernèche,
A gate in the selectivity filter of potassium channels.
2005,
Pubmed
Betto,
Interactions between permeation and gating in the TMEM16B/anoctamin2 calcium-activated chloride channel.
2014,
Pubmed
Bisha,
Metadynamics simulations reveal a Na+ independent exiting path of galactose for the inward-facing conformation of vSGLT.
2014,
Pubmed
Boiteux,
Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel.
2014,
Pubmed
Chakrabarti,
Catalysis of Na+ permeation in the bacterial sodium channel Na(V)Ab.
2013,
Pubmed
Cheng,
Mechanism for selectivity-inactivation coupling in KcsA potassium channels.
2011,
Pubmed
Chung,
TRPV1 shows dynamic ionic selectivity during agonist stimulation.
2008,
Pubmed
Collaborative Computational Project, Number 4,
The CCP4 suite: programs for protein crystallography.
1994,
Pubmed
Contreras,
Gating at the selectivity filter in cyclic nucleotide-gated channels.
2008,
Pubmed
Cordero-Morales,
Molecular driving forces determining potassium channel slow inactivation.
2007,
Pubmed
,
Xenbase
Cordero-Morales,
A multipoint hydrogen-bond network underlying KcsA C-type inactivation.
2011,
Pubmed
,
Xenbase
Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed
Craven,
CNG and HCN channels: two peas, one pod.
2006,
Pubmed
Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed
Cuello,
Structural basis for the coupling between activation and inactivation gates in K(+) channels.
2010,
Pubmed
Darré,
Permeation and dynamics of an open-activated TRPV1 channel.
2015,
Pubmed
Derebe,
Structural studies of ion permeation and Ca2+ blockage of a bacterial channel mimicking the cyclic nucleotide-gated channel pore.
2011,
Pubmed
Derebe,
Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites.
2011,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Emsley,
Features and development of Coot.
2010,
Pubmed
Furini,
Nonselective conduction in a mutated NaK channel with three cation-binding sites.
2012,
Pubmed
Furini,
Gating at the selectivity filter of ion channels that conduct Na+ and K+ ions.
2011,
Pubmed
Furini,
On conduction in a bacterial sodium channel.
2012,
Pubmed
Gamel,
The interaction of Na(+) and K(+) in the pore of cyclic nucleotide-gated channels.
2000,
Pubmed
,
Xenbase
Granata,
Characterization of the free-energy landscapes of proteins by NMR-guided metadynamics.
2013,
Pubmed
Hackos,
Divalent cation selectivity is a function of gating in native and recombinant cyclic nucleotide-gated ion channels from retinal photoreceptors.
1999,
Pubmed
,
Xenbase
Higgins,
Molecular architecture of a retinal cGMP-gated channel: the arrangement of the cytoplasmic domains.
2002,
Pubmed
Hille,
Ionic channels in excitable membranes. Current problems and biophysical approaches.
1978,
Pubmed
Holmgren,
Influence of permeant ions on gating in cyclic nucleotide-gated channels.
2003,
Pubmed
Holmgren,
The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge.
1998,
Pubmed
Hoshi,
C-type inactivation of voltage-gated K+ channels: pore constriction or dilation?
2013,
Pubmed
Jiang,
The open pore conformation of potassium channels.
2002,
Pubmed
Joosten,
PDB_REDO: constructive validation, more than just looking for errors.
2012,
Pubmed
Jójárt,
Performance of the general amber force field in modeling aqueous POPC membrane bilayers.
2007,
Pubmed
Jójárt,
Activation mechanism of the human histamine H4 receptor--an explicit membrane molecular dynamics simulation study.
2008,
Pubmed
Kabsch,
Integration, scaling, space-group assignment and post-refinement.
2010,
Pubmed
Kabsch,
XDS.
2010,
Pubmed
Karplus,
Linking crystallographic model and data quality.
2012,
Pubmed
Kaupp,
Cyclic nucleotide-gated ion channels.
2002,
Pubmed
Kusch,
Effects of permeating ions and cGMP on gating and conductance of rod-type cyclic nucleotide-gated (CNGA1) channels.
2004,
Pubmed
,
Xenbase
Laio,
Physical origin of selectivity in ionic channels of biological membranes.
1999,
Pubmed
Leslie,
The integration of macromolecular diffraction data.
2006,
Pubmed
Liu,
Gated access to the pore of a voltage-dependent K+ channel.
1997,
Pubmed
Loboda,
Dilated and defunct K channels in the absence of K+.
2001,
Pubmed
Lolicato,
Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
2011,
Pubmed
,
Xenbase
Marchesi,
Gating of cyclic nucleotide-gated channels is voltage dependent.
2012,
Pubmed
Mazzolini,
Gating in CNGA1 channels.
2010,
Pubmed
Morais-Cabral,
Energetic optimization of ion conduction rate by the K+ selectivity filter.
2001,
Pubmed
Murshudov,
REFMAC5 for the refinement of macromolecular crystal structures.
2011,
Pubmed
Ostmeyer,
Recovery from slow inactivation in K+ channels is controlled by water molecules.
2013,
Pubmed
Piana,
A bias-exchange approach to protein folding.
2007,
Pubmed
Picco,
The permeability of the cGMP-activated channel to organic cations in retinal rods of the tiger salamander.
1993,
Pubmed
Rodriguez,
Machine learning. Clustering by fast search and find of density peaks.
2014,
Pubmed
Ruiz,
Single cyclic nucleotide-gated channels locked in different ligand-bound states.
1997,
Pubmed
,
Xenbase
Sauer,
Protein interactions central to stabilizing the K+ channel selectivity filter in a four-sited configuration for selective K+ permeation.
2011,
Pubmed
Sauer,
Sodium and potassium competition in potassium-selective and non-selective channels.
2013,
Pubmed
Schulz,
Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
2010,
Pubmed
Shuart,
Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels.
2011,
Pubmed
Strong,
Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis.
2006,
Pubmed
Yeates,
Detecting and overcoming crystal twinning.
1997,
Pubmed
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
Zhang,
TM-align: a protein structure alignment algorithm based on the TM-score.
2005,
Pubmed
Zhou,
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.
2001,
Pubmed
