Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I
Abstract Voltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaV isoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors ar...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55764-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861815230070784 |
|---|---|
| author | Bryan Neumann Stephen McCarthy Shane Gonen |
| author_facet | Bryan Neumann Stephen McCarthy Shane Gonen |
| author_sort | Bryan Neumann |
| collection | DOAJ |
| description | Abstract Voltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaV isoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-NaV1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDI was unresolvable. We find that Protoxin-I binds to and displaces the VSDII S3-S4 linker, hindering translocation of the S4II helix during activation. |
| format | Article |
| id | doaj-art-787d8e8be25f4201ba255bd1430bbd63 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-787d8e8be25f4201ba255bd1430bbd632025-02-09T12:44:55ZengNature PortfolioNature Communications2041-17232025-02-0116111010.1038/s41467-024-55764-zStructural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-IBryan Neumann0Stephen McCarthy1Shane Gonen2Department of Molecular Biology and Biochemistry, University of California IrvineDepartment of Molecular Biology and Biochemistry, University of California IrvineDepartment of Molecular Biology and Biochemistry, University of California IrvineAbstract Voltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaV isoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-NaV1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDI was unresolvable. We find that Protoxin-I binds to and displaces the VSDII S3-S4 linker, hindering translocation of the S4II helix during activation.https://doi.org/10.1038/s41467-024-55764-z |
| spellingShingle | Bryan Neumann Stephen McCarthy Shane Gonen Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I Nature Communications |
| title | Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I |
| title_full | Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I |
| title_fullStr | Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I |
| title_full_unstemmed | Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I |
| title_short | Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I |
| title_sort | structural basis of inhibition of human nav1 8 by the tarantula venom peptide protoxin i |
| url | https://doi.org/10.1038/s41467-024-55764-z |
| work_keys_str_mv | AT bryanneumann structuralbasisofinhibitionofhumannav18bythetarantulavenompeptideprotoxini AT stephenmccarthy structuralbasisofinhibitionofhumannav18bythetarantulavenompeptideprotoxini AT shanegonen structuralbasisofinhibitionofhumannav18bythetarantulavenompeptideprotoxini |