Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel
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 mutation...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-08-01
|
| Series: | Insects |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-4450/13/8/745 |
| _version_ | 1797444502203400192 |
|---|---|
| author | Boris S. Zhorov Ke Dong |
| author_facet | Boris S. Zhorov Ke Dong |
| author_sort | Boris S. Zhorov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T13:12:32Z |
| format | Article |
| id | doaj.art-60ac56d620144510a12c67b11df5c18e |
| institution | Directory Open Access Journal |
| issn | 2075-4450 |
| language | English |
| last_indexed | 2024-03-09T13:12:32Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Insects |
| spelling | doaj.art-60ac56d620144510a12c67b11df5c18e2023-11-30T21:39:33ZengMDPI AGInsects2075-44502022-08-0113874510.3390/insects13080745Pyrethroids in an AlphaFold2 Model of the Insect Sodium ChannelBoris S. Zhorov0Ke Dong1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, CanadaDepartment of Biology, Duke University, Durham, NC 27708, USAPyrethroid 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.https://www.mdpi.com/2075-4450/13/8/745pyrethroidsinsecticidessodium channelchannel gatingkdr mutations |
| spellingShingle | Boris S. Zhorov Ke Dong Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel Insects pyrethroids insecticides sodium channel channel gating kdr mutations |
| title | Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel |
| title_full | Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel |
| title_fullStr | Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel |
| title_full_unstemmed | Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel |
| title_short | Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel |
| title_sort | pyrethroids in an alphafold2 model of the insect sodium channel |
| topic | pyrethroids insecticides sodium channel channel gating kdr mutations |
| url | https://www.mdpi.com/2075-4450/13/8/745 |
| work_keys_str_mv | AT borisszhorov pyrethroidsinanalphafold2modeloftheinsectsodiumchannel AT kedong pyrethroidsinanalphafold2modeloftheinsectsodiumchannel |