Editors' ChoiceStructural Biology

A channel involved in pain perception

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Sci. Signal.  22 Dec 2015:
Vol. 8, Issue 408, pp. ec382
DOI: 10.1126/scisignal.aaf1072

Voltage-gated sodium (Nav) channels propagate electrical signals in muscle cells and neurons. In humans, Nav1.7 plays a key role in pain perception. It is challenging to target a particular Nav isoform; however, arylsulfonamide antagonists selective for Nav1.7 have been reported recently. Ahuja et al. characterized the binding of these small molecules to human Nav channels. To further investigate the mechanism, they engineered a bacterial Nav channel to contain features of the Nav1.7 voltage-sensing domain that is targeted by the antagonist and determined the crystal structure of the chimera bound to an inhibitor. The structure gives insight into the mechanism of voltage sensing and will enable the design of more selective Nav channel antagonists.

S. Ahuja, S. Mukund, L. Deng, K. Khakh, E. Chang, H. Ho, S. Shriver, C. Young, S. Lin, J. P. Johnson Jr., P. Wu, J. Li, M. Coons, C. Tam, B. Brillantes, H. Sampang, K. Mortara, K. K. Bowman, K. R. Clark, A. Estevez, Z. Xie, H. Verschoof, M. Grimwood, C. Dehnhardt, J.-C. Andrez, T. Focken, D. P. Sutherlin, B. S. Safina, M. A. Starovasnik, D. F. Ortwine, Y. Franke, C. J. Cohen, D. H. Hackos, C. M. Koth, J. Payandeh, Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science 350, aac5464 (2015). [Abstract] [Full Text]