Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist

Abstract

A channel involved in pain perception 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. Science , this issue p. 10.1126/science.aac5464

On the role of water density fluctuations in the inhibition of a proton channel

“…Ion channels are responsible for a number of channelopathies (i.e., pathological conditions of various origins), including genetic channelopathies caused by malfunctioning ion channels (78). Nevertheless, despite recent efforts resulting in the discovery of novel potential drugs targeting ion channels (39,40), this class of proteins remains quite underexploited in drug discovery because it poses significant challenges (78)(79)(80)(81). For many years,…”

“…Finally, substrate-mimicking strategies, traditionally adopted for enzymes, are hardly an option for ion channels: Competition with the permeant ion in the selectivity filter can be attained only by another ion or by small fragments. Recent advances in the biophysical characterization and screening of ion channels, together with continuing progress in biomolecular simulations, have paved the way for successful drug design campaigns (39,40,82) that have made ion channels pharmaceutically tractable, as well as attractive, targets. Notably, targeting ion channels increased the therapeutic options in areas such as cardiovascular diseases, neuropathic pain, diabetes, and cancer (79,81).…”

“…Despite being perceived as challenging targets, ion channels are amenable to rational drug design, as shown by recent success stories (39,40). A prominent example is the M2 proton channel of the influenza A virus, a drug target showing striking similarities to Hv1.…”

Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development

“…4, D and E). The X-ray crystallographic structure of Na V Ab-hNa V 1.7-VSD-IV chimera shows a phosphatidylcholine (23) bound to the same region of the structure where Gly-856 is positioned in our structural model. Interaction of the phosphodiester head groups of lipids are essential for voltage-dependent gating (24,25), suggesting that alteration of the lipid-channel interaction may modulate Na V channel function.…”

Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNa V 1.7

“…8-10). The detailed view of toxin binding, however, is unsupported by structural biology, as no high-resolution structure of a eukaryotic Na V has been solved to date (11)(12)(13)(14)(15)(16). Na V homology models, constructed based on X-ray analyses of prokaryotic Na + and K + voltage-gated channels, do not sufficiently account for experimental structure-activity relationship (SAR) data (6,(17)(18)(19)(20), and the molecular details underlying distinct differences in toxin potencies toward individual Na V subtypes remain undefined (5,6,(21)(22)(23).…”