Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel

• Published in: Nature (London) Vol. 486; no. 7401; pp. 130 - 134
• Main Authors: Zhang, Xu, Ren, Wenlin, DeCaen, Paul, Yan, Chuangye, Tao, Xiao, Tang, Lin, Wang, Jingjing, Hasegawa, Kazuya, Kumasaka, Takashi, He, Jianhua, Wang, Jiawei, Clapham, David E., Yan, Nieng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-06-2012; Nature Publishing Group
• Subjects: 631/378/2586; 631/45/269/1152; 631/45/535; Action potentials (Electrophysiology); Activation; Alphaproteobacteria - chemistry; Amino Acid Sequence; Bacteria; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biological and medical sciences; Channels; Crystal structure; Crystalline structure; Crystallization; Crystallography, X-Ray; Crystals; Depolarization; Experiments; Filters (fluid); Fundamental and applied biological sciences. Psychology; HEK293 Cells; Humanities and Social Sciences; Humans; Ion Channel Gating; Ions; letter; Models, Molecular; Molecular biophysics; Molecular Sequence Data; multidisciplinary; Physiological aspects; Protein Conformation; Proteins; Science; Science (multidisciplinary); Selectivity; Sodium; Sodium channels; Sodium Channels - chemistry; Sodium Channels - metabolism; Structure; Structure in molecular biology; Structure-Activity Relationship; United States; Japan; China; Ionic channel; Voltage-gated canal; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11054

The crystal structure of Na
v
Rh, a NaChBac orthologue from the marine
Rickettsiales sp. HIMB114
, defines an ion binding site within the selectivity filter, and reveals several conformational rearrangements that may underlie the electromechanical coupling mechanism.
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.
Voltage-gated sodium (Na
v
) channels are essential for the rapid depolarization of nerve and muscle
1
, and are important drug targets
2
. Determination of the structures of Na
v
channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na
v
channels, exemplified by the Na
+
-selective channel of bacteria (NaChBac)
3
, provides a useful model system for structure–function analysis. Here we report the crystal structure of Na
v
Rh, a NaChBac orthologue from the marine
alphaproteobacterium HIMB114
(
Rickettsiales sp. HIMB114
; denoted Rh), at 3.05 Å resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca
2+
resides in the crystal structure. The outer mouth of the Na
+
selectivity filter, defined by Ser 181 and Glu 183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that Na
v
Rh is in an ‘inactivated’ conformation. Comparison of Na
v
Rh with Na
v
Ab
4
reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.