Scorpion α-toxin LqhαIT specifically interacts with a glycan at the pore domain of voltage-gated sodium channels.

Autor:	Phulera S; Discovery Sciences, Novartis Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA., Dickson CJ; Global Discovery Chemistry, Novartis Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA., Schwalen CJ; Global Discovery Chemistry, Novartis Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA., Khoshouei M; Discovery Sciences, Novartis Biomedical Research, Novartis Pharma AG, Basel, Switzerland., Cassell SJ; Discovery Sciences, Novartis Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA., Sun Y; Neuroscience, Novartis Biomedical Research, 22 Windsor St, Cambridge, MA 02139, USA., Condos T; Discovery Sciences, Novartis Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA., Whicher J; Discovery Sciences, Novartis Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: jonathan.whicher@novartis.com., Weihofen WA; Discovery Sciences, Novartis Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: wilhelm.weihofen@novartis.com.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2024 Oct 03; Vol. 32 (10), pp. 1611-1620.e4. Date of Electronic Publication: 2024 Aug 23.
DOI:	10.1016/j.str.2024.07.021
Abstrakt:	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. Competing Interests: Declaration of interests All authors are/were employees of Novartis. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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