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TitleStructural mapping of Na1.7 antagonists.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3224, Year 2023
Publish dateJun 3, 2023
AuthorsQiurong Wu / Jian Huang / Xiao Fan / Kan Wang / Xueqin Jin / Gaoxingyu Huang / Jiaao Li / Xiaojing Pan / Nieng Yan /
PubMed AbstractVoltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in ...Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures.
External linksNat Commun / PubMed:37270609 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 3.2 Å
Structure data

35193

8i5b

EMDB-35193, PDB-8i5b:
Structure of human Nav1.7 in complex with bupivacaine
Method: EM (single particle) / Resolution: 2.7 Å

35194

8i5g

EMDB-35194, PDB-8i5g:
Structure of human Nav1.7 in complex with PF-05089771
Method: EM (single particle) / Resolution: 2.7 Å

35197

8i5x

EMDB-35197, PDB-8i5x:
Structure of human Nav1.7 in complex with Vinpocetine
Method: EM (single particle) / Resolution: 2.9 Å

35198

8i5y

EMDB-35198, PDB-8i5y:
Structure of human Nav1.7 in complex with vixotrigine
Method: EM (single particle) / Resolution: 2.6 Å

35975

8j4f

EMDB-35975, PDB-8j4f:
Structure of human Nav1.7 in complex with Hardwickii acid
Method: EM (single particle) / Resolution: 3.0 Å

40238

8s9b

EMDB-40238, PDB-8s9b:
Cryo-EM structure of Nav1.7 with LCM
Method: EM (single particle) / Resolution: 2.9 Å

40239

8s9c

EMDB-40239, PDB-8s9c:
Cryo-EM structure of Nav1.7 with CBZ
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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

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-OJ0:
Levobupivacaine

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-T70:
PF-05089771

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-T7F:
Vinpocetine

ChemComp-TB4:
Vixotrigine

ChemComp-1PW:
(2S,3R,4E)-2-(acetylamino)-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate

ChemComp-UK0:
(4~{a}~{R},5~{S},6~{R},8~{a}~{R})-5-[2-(furan-3-yl)ethyl]-5,6,8~{a}-trimethyl-3,4,4~{a},6,7,8-hexahydronaphthalene-1-carboxylic acid

ChemComp-LQO:
lacosamide

ChemComp-N6W:
benzo[b][1]benzazepine-11-carboxamide / medication*YM

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

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