8THH

Cryo-EM structure of Nav1.7 with LTG

Summary for 8THH

• Entry DOI: 10.2210/pdb8thh/pdb
• EMDB information: 41262
• Descriptor: Sodium channel protein type 9 subunit alpha, O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine, Sodium channel subunit beta-1, ... (11 entities in total)
• Functional Keywords: cryo-em, sodium channel, vgsc, nav1.7, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 286764.04

Authors

Fan, X.,Huang, J.,Yan, N. (deposition date: 2023-07-16, release date: 2023-11-22, Last modification date: 2024-11-20)

Primary citation

Huang, J.,Fan, X.,Jin, X.,Teng, L.,Yan, N.
Dual-pocket inhibition of Na v channels by the antiepileptic drug lamotrigine.
Proc.Natl.Acad.Sci.USA, 120:e2309773120-e2309773120, 2023

PubMed Abstract: Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na 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 Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å 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 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 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.

PubMed: 37782796
DOI: 10.1073/pnas.2309773120

Experimental method

ELECTRON MICROSCOPY (2.7 Å)