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

Abstract

Voltage-gated sodium (Nav) channels are essential for the rapid depolarization of nerve and muscle1, and are important drug targets2. Determination of the structures of Nav channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Nav 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 NavRh, 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 Ca2+ 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 NavRh is in an ‘inactivated’ conformation. Comparison of NavRh with NavAb4 reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.

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Figure 1: The structure of Na v Rh exhibits a closed conformation.
Figure 2: A Ca 2+ ion is bound in the asymmetric selectivity filter of Na v Rh.
Figure 3: The VSDs of Na v Rh exhibit a depolarized conformation.
Figure 4: Molecular basis of charge transfer of VSDs.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates of NavRh are deposited in Protein Data Bank under accession number 4DXW.

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Acknowledgements

We thank R. MacKinnon at Rockefeller University for discussions and reading the manuscript. We thank L. Feng at Rockefeller University for help. We thank S. Huang and F. Yu at Shanghai Synchrotron Radiation Facility beamline BL17U. K.H. acknowledges SPring-8 beamline BL41XU for proposal 2011A2039. This work was supported by funds from the Ministry of Science and Technology (grant numbers 2009CB918802, 2011CB910501 and 2011CB911102), projects 31125009 and 91017011 of the National Natural Science Foundation of China, and funds from Tsinghua University.

Author information

X.Z., W.R., P.D., X.T., D.E.C. and N.Y. designed experiments. X.Z., W.R., P.D., C.Y., X.T., L.T., J.W., K.H., T.K., J.H., J.W. and N.Y. performed the experiments. X.Z., W.R., P.D., C.Y., X.T., J.W., D.E.C. and N.Y. analysed the data. X.Z., P.D., X.T., C.Y., J.W. and D.E.C. contributed to manuscript preparation. N.Y. wrote the manuscript.

Correspondence to Nieng Yan.

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This file contains Supplementary Figures 1-10, Supplementary Tables 1-2 and the full legend for Supplementary Movie 1. (PDF 3407 kb)

Supplementary Movie

This file contains Supplementary Movie 1 which illustrates the structural basis for gating charge transfer. (MPG 16744 kb)

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Zhang, X., Ren, W., DeCaen, P. et al. Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature 486, 130–134 (2012). https://doi.org/10.1038/nature11054

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