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The crystal structure of a voltage-gated sodium channel
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Journal Article
The crystal structure of a voltage-gated sodium channel
2011
Overview
Voltage-gated sodium (Na
V
) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na
+
channel from
Arcobacter butzleri
(NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 Å resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4–S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ∼4.6 Å wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na
+
selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level.
Mechanism of Na+ channel action
The X-ray crystal structure of a voltage-gated sodium channel from
Arcobacter butzleri
has been determined, with the channel in the closed-pore conformation. Channels of this type initiate electrical signalling in excitable cells and are the molecular targets for many drugs, but the structural basis for their voltage-dependent activation and ion selectivity is not known. The selectivity filter in this sodium channel is found to be quite short, compared with those in open-pore potassium channels, and the voltage-sensor domains and linkers between segments S4 and S5 seem to dilate the central pore by pivoting together.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Bacterial Proteins - chemistry
/ Bacterial Proteins - metabolism
/ Biological and medical sciences
/ Crystals
/ Humanities and Social Sciences
/ Hydrophobic and Hydrophilic Interactions
/ Pharmaceutical technology. Pharmaceutical industry
/ Pharmacology. Drug treatments
/ Potassium Channels - chemistry
/ Potassium Channels - metabolism
/ Proteins
/ Science
/ Sodium
/ Sodium Channel Blockers - chemistry
/ Sodium Channel Blockers - metabolism
/ Sodium Channel Blockers - pharmacology
/ Sodium Channels - metabolism
