Mapping the Molecular Surface of the Analgesic Na_V1.7-Selective Peptide Pn3a Reveals Residues Essential for Membrane and Channel Interactions.

ABSTRACT: Compelling human genetic studies have identified the voltage-gated sodium channel Na_V1.7 as a promising therapeutic target for the treatment of pain. The analgesic spider-venom-derived peptide μ-theraphotoxin-Pn3a is an exceptionally potent and selective inhibitor of Na_V1.7; however, little is known about the structure-activity relationships or channel interactions that define this activity. We rationally designed 17 Pn3a analogues and determined their activity at hNa_V1.7 using patch-clamp electrophysiology. The positively charged amino acids K22 and K24 were identified as crucial for Pn3a activity, with molecular modeling identifying interactions of these residues with the S3-S4 loop of domain II of hNa_V1.7. Removal of hydrophobic residues Y4, Y

SUBMITTER: Mueller A 

PROVIDER: S-EPMC7296542 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature