Crystal structure of a voltage-gated sodium channel in two potentially inactivated states

• Published in: Nature (London) Vol. 486; no. 7401; pp. 135 - 139
• Main Authors: Payandeh, Jian, Gamal El-Din, Tamer M., Scheuer, Todd, Zheng, Ning, Catterall, William A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2012; Nature Publishing Group
• Subjects: 631/378/2586; 631/443/376; 631/45/269/1152; 631/45/535; Amino acids; Arcobacter - chemistry; Biological and medical sciences; Carbonyl compounds; Conserved Sequence; Crystalline structure; Crystallization; Crystallography, X-Ray; Crystals; Fundamental and applied biological sciences. Psychology; Genetic aspects; Geometry; Humanities and Social Sciences; Inactivation; Ion Channel Gating; Ion channels; letter; Membrane potentials; Models, Molecular; Molecular biophysics; multidisciplinary; Mutation; Physiological aspects; Protein Conformation; Science; Science (multidisciplinary); Sodium Channels - chemistry; Sodium Channels - metabolism; Structure; Structure in molecular biology; Structure-Activity Relationship; United States; Prokaryote; Bacteria; Voltage-gated canal; Microorganism; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11077

X-ray crystal structures of a bacterial voltage-gated sodium channel in two ‘inactivated’ conformations are reported, revealing several conformational rearrangements that may underlie the electromechanical coupling of voltage sensor movement to inactivation of the pore. High-resolution sodium channel structures There are many published structures for potassium channels, but structural information on voltage-gated sodium (Na v ) channels is much more scare, despite their importance in the initiation and propagation of action potentials in nerve cells, muscle cells and in the heart. Bacterial Na v channels provide a good model system for structure–function analyses, and here two groups report the X-ray crystal structure of bacterial Na v channels apparently in 'inactivated' conformations. Nieng Yan and colleagues determined the structure of Na v Rh from the marine bacterium known as alpha proteobacterium HIMB114 at 3.05-ångström resolution. William Catterall and colleagues report crystallographic snapshots of the Na v Ab channel from Arcobacter butzleri in two potentially inactivated states at 3.2-ångström resolution. Comparisons of these newly obtained structures with previously published data on Na v Ab in a 'pre-open' state reveal conformational rearrangements that may underlie the electromechanical coupling mechanism of these channels. This work is relevant to channelopathies and more widely to the design of neuroactive drugs. In excitable cells, voltage-gated sodium (Na V ) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance 1 , 2 . Inactivation is a hallmark of Na V channel function and is critical for control of membrane excitability 3 , but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na V Ab channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 Å resolution. Compared to previous structures of Na V Ab channels with cysteine mutations in the pore-lining S6 helices (ref. 4 ), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na V Ab models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na V Ab, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na V channel gating and inactivation. These potential inactivated-state structures provide new insights into Na V channel gating and novel avenues to drug development and therapy for a range of debilitating Na V channelopathies.