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Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel.

Publication ,  Journal Article
Zhorov, BS; Dong, K
Published in: Insects
August 2022

Pyrethroid insecticides stabilize the open state of insect sodium channels. Previous mutational, electrophysiological, and computational analyses led to the development of homology models predicting two pyrethroid receptor sites, PyR1 and PyR2. Many of the naturally occurring sodium channel mutations, which confer knockdown resistance (kdr) to pyrethroids, are located within or close to these receptor sites, indicating that these mutations impair pyrethroid binding. However, the mechanism of the state-dependent action of pyrethroids and the mechanisms by which kdr mutations beyond the receptor sites confer resistance remain unclear. Recent advances in protein structure prediction using the AlphaFold2 (AF2) neural network allowed us to generate a new model of the mosquito sodium channel AaNav1-1, with the activated voltage-sensing domains (VSMs) and the presumably inactivated pore domain (PM). We further employed Monte Carlo energy minimizations to open PM and deactivate VSM-I and VSM-II to generate additional models. The docking of a Type II pyrethroid deltamethrin in the models predicted its interactions with many known pyrethroid-sensing residues in the PyR1 and PyR2 sites and revealed ligand-channel interactions that stabilized the open PM and activated VSMs. Our study confirms the predicted two pyrethroid receptor sites, explains the state-dependent action of pyrethroids, and proposes the mechanisms of the allosteric effects of various kdr mutations on pyrethroid action. The AF2-based models may assist in the structure-based design of new insecticides.

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Published In

Insects

DOI

EISSN

2075-4450

ISSN

2075-4450

Publication Date

August 2022

Volume

13

Issue

8

Start / End Page

745

Related Subject Headings

  • 3109 Zoology
  • 0608 Zoology
 

Citation

APA
Chicago
ICMJE
MLA
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Zhorov, B. S., & Dong, K. (2022). Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel. Insects, 13(8), 745. https://doi.org/10.3390/insects13080745
Zhorov, Boris S., and Ke Dong. “Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel.Insects 13, no. 8 (August 2022): 745. https://doi.org/10.3390/insects13080745.
Zhorov BS, Dong K. Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel. Insects. 2022 Aug;13(8):745.
Zhorov, Boris S., and Ke Dong. “Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel.Insects, vol. 13, no. 8, Aug. 2022, p. 745. Epmc, doi:10.3390/insects13080745.
Zhorov BS, Dong K. Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel. Insects. 2022 Aug;13(8):745.

Published In

Insects

DOI

EISSN

2075-4450

ISSN

2075-4450

Publication Date

August 2022

Volume

13

Issue

8

Start / End Page

745

Related Subject Headings

  • 3109 Zoology
  • 0608 Zoology