8FEY

Solution structure of Pmu1a

Summary for 8FEY

• Entry DOI: 10.2210/pdb8fey/pdb
• NMR Information: BMRB: 31063
• Descriptor: Pmu1a toxin (1 entity in total)
• Functional Keywords: spider, voltage-gated channels, toxin
• Biological source: Pterinochilus murinus
• Total number of polymer chains: 1
• Total formula weight: 4367.01

Authors

Daly, N.L.,Wilson, D.T. (deposition date: 2022-12-07, release date: 2023-03-29, Last modification date: 2024-11-06)

Primary citation

Giribaldi, J.,Chemin, J.,Tuifua, M.,Deuis, J.R.,Mary, R.,Vetter, I.,Wilson, D.T.,Daly, N.L.,Schroeder, C.I.,Bourinet, E.,Dutertre, S.
Pmu1a, a novel spider toxin with dual inhibitory activity at pain targets hNa V 1.7 and hCa V 3 voltage-gated channels.
Febs J., 290:3688-3702, 2023

PubMed Abstract: Venom-derived peptides targeting ion channels involved in pain are regarded as a promising alternative to current, and often ineffective, chronic pain treatments. Many peptide toxins are known to specifically and potently block established therapeutic targets, among which the voltage-gated sodium and calcium channels are major contributors. Here, we report on the discovery and characterization of a novel spider toxin isolated from the crude venom of Pterinochilus murinus that shows inhibitory activity at both hNa 1.7 and hCa 3.2 channels, two therapeutic targets implicated in pain pathways. Bioassay-guided HPLC fractionation revealed a 36-amino acid peptide with three disulfide bridges named μ/ω-theraphotoxin-Pmu1a (Pmu1a). Following isolation and characterization, the toxin was chemically synthesized and its biological activity was further assessed using electrophysiology, revealing Pmu1a to be a toxin that potently blocks both hNa 1.7 and hCa 3. Nuclear magnetic resonance structure determination of Pmu1a shows an inhibitor cystine knot fold that is the characteristic of many spider peptides. Combined, these data show the potential of Pmu1a as a basis for the design of compounds with dual activity at the therapeutically relevant hCa 3.2 and hNa 1.7 voltage-gated channels.

PubMed: 36912793
DOI: 10.1111/febs.16773

Experimental method

SOLUTION NMR