Publication Date:
2011-07-12
Description:
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 A 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, approximately 4.6 A 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266868/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payandeh, Jian -- Scheuer, Todd -- Zheng, Ning -- Catterall, William A -- R01 NS015751/NS/NINDS NIH HHS/ -- R01 NS015751-24/NS/NINDS NIH HHS/ -- R01 NS15751/NS/NINDS NIH HHS/ -- U01 NS058039/NS/NINDS NIH HHS/ -- U01 NS058039-03/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 10;475(7356):353-8. doi: 10.1038/nature10238.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21743477" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Arcobacter/*chemistry
;
Bacterial Proteins/*chemistry/*metabolism
;
Binding Sites
;
Calcium/metabolism
;
Cell Membrane/metabolism
;
Crystallography, X-Ray
;
Hydrophobic and Hydrophilic Interactions
;
*Ion Channel Gating
;
Ion Transport
;
Models, Molecular
;
Potassium/metabolism
;
Potassium Channels/chemistry/metabolism
;
Protein Conformation
;
Sodium/metabolism
;
Sodium Channel Blockers/chemistry/metabolism/pharmacology
;
Sodium Channels/*chemistry/*metabolism
;
Structure-Activity Relationship
;
Substrate Specificity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
