8thh | pdb_00008thh
Cryo-EM structure of Nav1.7 with LTG
Structural highlights
DiseaseSCN2B_HUMAN Familial atrial fibrillation. The disease is caused by mutations affecting the gene represented in this entry. Genetic variations in SCN2B may be involved in Brugada syndrome (PubMed:23559163). This tachyarrhythmia is characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.[1] FunctionSCN2B_HUMAN Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier (By similarity). Publication Abstract from PubMedVoltage-gated sodium (Na(v)) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na(v) channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na(v)1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 A and 2.7 A, respectively. A 3D EM reconstruction of ligand-free Na(v)1.7 was also obtained at 2.1 A resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na(v) channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na(v) channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs. Dual-pocket inhibition of Na(v) channels by the antiepileptic drug lamotrigine.,Huang J, Fan X, Jin X, Teng L, Yan N Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2309773120. doi: , 10.1073/pnas.2309773120. Epub 2023 Oct 2. PMID:37782796[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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