8VQC

Structure of the voltage-gated sodium channel NavPas from American Cockroach Periplaneta Americana in complex with scorpion alpha-toxin LqhaIT

Summary for 8VQC

• Entry DOI: 10.2210/pdb8vqc/pdb
• EMDB information: 43438
• Descriptor: Sodium channel protein PaFPC1, Alpha-insect toxin LqhaIT, beta-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: navpas, scorpion toxin, ion channel, voltage-gated sodium channel, membrane protein
• Biological source: Periplaneta americana (American cockroach); More
• Total number of polymer chains: 2
• Total formula weight: 194647.00

Authors

Phulera, S.,Khoshouei, M.,Whicher, J.,Weihofen, W.A. (deposition date: 2024-01-18, release date: 2024-09-04, Last modification date: 2024-11-13)

Primary citation

Phulera, S.,Dickson, C.J.,Schwalen, C.J.,Khoshouei, M.,Cassell, S.J.,Sun, Y.,Condos, T.,Whicher, J.,Weihofen, W.A.
Scorpion alpha-toxin Lqh alpha IT specifically interacts with a glycan at the pore domain of voltage-gated sodium channels.
Structure, 32:1611-1620.e4, 2024

PubMed Abstract: Voltage-gated sodium (Nav) channels sense membrane potential and drive cellular electrical activity. The deathstalker scorpion α-toxin LqhαIT exerts a strong action potential prolonging effect on Nav channels. To elucidate the mechanism of action of LqhαIT, we determined a 3.9 Å cryoelectron microscopy (cryo-EM) structure of LqhαIT in complex with the Nav channel from Periplaneta americana (NavPas). We found that LqhαIT binds to voltage sensor domain 4 and traps it in an "S4 down" conformation. The functionally essential C-terminal epitope of LqhαIT forms an extensive interface with the glycan scaffold linked to Asn330 of NavPas that augments a small protein-protein interface between NavPas and LqhαIT. A combination of molecular dynamics simulations, structural comparisons, and prior mutagenesis experiments demonstrates the functional importance of this toxin-glycan interaction. These findings establish a structural basis for the specificity achieved by scorpion α-toxins and reveal the conserved glycan as an essential component of the toxin-binding epitope.

PubMed: 39181123
DOI: 10.1016/j.str.2024.07.021

Experimental method

ELECTRON MICROSCOPY (3.9 Å)