8S6J
NavMs in complex with riluzole
Summary for 8S6J
| Entry DOI | 10.2210/pdb8s6j/pdb |
| Descriptor | Ion transport protein, SODIUM ION, 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine, ... (7 entities in total) |
| Functional Keywords | voltage-gated sodium channel, membrane protein |
| Biological source | Magnetococcus marinus MC-1 |
| Total number of polymer chains | 1 |
| Total formula weight | 32205.62 |
| Authors | Hollingworth, D.,Sula, A.,Mykhaylyk, V.,Wallace, B.A. (deposition date: 2024-02-27, release date: 2024-09-18, Last modification date: 2024-10-09) |
| Primary citation | Hollingworth, D.,Thomas, F.,Page, D.A.,Fouda, M.A.,De Castro, R.L.,Sula, A.,Mykhaylyk, V.B.,Kelly, G.,Ulmschneider, M.B.,Ruben, P.C.,Wallace, B.A. Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole. Nat Commun, 15:8426-8426, 2024 Cited by PubMed Abstract: Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (I). I results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of I that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of I without the physical block of Na conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased I is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing. PubMed: 39341837DOI: 10.1038/s41467-024-52539-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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