6X8R

Pharmacological characterisation and NMR structure of the novel mu-conotoxin SxIIIC, a potent irreversible NaV channel inhibitor

Summary for 6X8R

• Entry DOI: 10.2210/pdb6x8r/pdb
• NMR Information: BMRB: 30758
• Descriptor: SxIIIC peptide (1 entity in total)
• Functional Keywords: sodium channels, toxin
• Biological source: Conus striolatus
• Total number of polymer chains: 1
• Total formula weight: 2447.84

Authors

Schroeder, C.I.,McMahon, K.L. (deposition date: 2020-06-01, release date: 2020-10-21, Last modification date: 2024-10-23)

Primary citation

McMahon, K.L.,Tran, H.N.T.,Deuis, J.R.,Lewis, R.J.,Vetter, I.,Schroeder, C.I.
Discovery, Pharmacological Characterisation and NMR Structure of the Novel μ-Conotoxin SxIIIC, a Potent and Irreversible Na V Channel Inhibitor.
Biomedicines, 8:-, 2020

PubMed Abstract: Voltage-gated sodium (Na) channel subtypes, including Na1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins characterised so far, only a small number, including KIIIA and CnIIIC, have shown inhibition against human Na1.7. We have recently identified a novel µ-conotoxin, SxIIIC, from . Here we present the isolation of native peptide, chemical synthesis, characterisation of human Na channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 >> 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human Na1.7 putative pore blockers (IC 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for Na channel pore blocker selectivity and subsequently important for chronic pain drug development.

PubMed: 33023152
DOI: 10.3390/biomedicines8100391

Experimental method

SOLUTION NMR