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Structure of VSD4-NaV1.7-NaVPas channel chimera bound to the arylsulfonamide inhibitor GNE-3565Structure of VSD4-NaV1.7-NaVPas channel chimera bound to the arylsulfonamide inhibitor GNE-3565
Structural highlights
DiseaseSCN9A_HUMAN Channelopathy-associated congenital insensitivity to pain;Dravet syndrome;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Generalized epilepsy with febrile seizures-plus;Hereditary sensory and autonomic neuropathy type 2;Paroxysmal extreme pain disorder;Erythromelalgia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionSCN9A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] SCNA1_PERAM Mediates the voltage-dependent sodium ion permeability of excitable membranes.[RuleBase:RU361132][11] Publication Abstract from PubMedThe voltage-gated sodium (Na(V)) channel Na(V)1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na(V) channel blocking drugs are not selective among the nine Na(V) channel subtypes, Na(V)1.1-Na(V)1.9. Moreover, the two currently known classes of Na(V)1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of Na(V)1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the Na(V)1.7 channel, we pursued high-resolution ligand-bound Na(V)1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the Na(V)1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in Na(V) channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design This work also underscores an important role of the membrane bilayer in the optimization of selective Na(V) channel modulators targeting VSD4. Cryo-EM reveals an unprecedented binding site for Na(V)1.7 inhibitors enabling rational design of potent hybrid inhibitors.,Kschonsak M, Jao CC, Arthur CP, Rohou AL, Bergeron P, Ortwine DF, McKerrall SJ, Hackos DH, Deng L, Chen J, Li T, Dragovich PS, Volgraf M, Wright MR, Payandeh J, Ciferri C, Tellis JC Elife. 2023 Mar 28;12:e84151. doi: 10.7554/eLife.84151. PMID:36975198[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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