Structural basis for modulation of human Na<sub>V</sub>1.3 by clinical drug and selective antagonist.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35277491.
- Also identified by DOI 10.1038/s41467-022-28808-5 and PMC identifier 8917200.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Voltage-gated sodium (Na<sub>V</sub>) channels play fundamental roles in initiating and propagating action potentials. Na<sub>V</sub>1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na<sub>V</sub>1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na<sub>V</sub> channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na<sub>V</sub> channels and pave a way for subtype-selective therapeutic development.
Medical subject headings
- NAV1.7 Voltage-Gated Sodium Channel
- Voltage-Gated Sodium Channel Blockers