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TitleDual-pocket inhibition of Na channels by the antiepileptic drug lamotrigine.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 120, Issue 41, Page e2309773120, Year 2023
Publish dateOct 10, 2023
AuthorsJian Huang / Xiao Fan / Xueqin Jin / Liming Teng / Nieng Yan /
PubMed AbstractVoltage-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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:37782796 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 2.9 Å
Structure data

41261

8thg

EMDB-41261, PDB-8thg:
Cryo-EM structure of Nav1.7 with RLZ
Method: EM (single particle) / Resolution: 2.9 Å

41262

8thh

EMDB-41262, PDB-8thh:
Cryo-EM structure of Nav1.7 with LTG
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-657:
6-(trifluoromethoxy)-1,3-benzothiazol-2-amine / medication*YM / Riluzole

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / Phosphatidylserine

ChemComp-HOH:
WATER / Water

ChemComp-IYJ:
(6M)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Cryo-EM / sodium channel / VGSC / Nav1.7

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