7SAV

Native mu-conotoxin KIIIA isomer

Summary for 7SAV

• Entry DOI: 10.2210/pdb7sav/pdb
• NMR Information: BMRB: 30953
• Descriptor: Mu-conotoxin KIIIA (1 entity in total)
• Functional Keywords: disulfide isomer, toxin
• Biological source: Conus kinoshitai (Kinoshita's cone)
• Total number of polymer chains: 1
• Total formula weight: 1893.23

Authors

Schroeder, C.I.,Tran, H.N.T. (deposition date: 2021-09-23, release date: 2022-05-25, Last modification date: 2024-11-20)

Primary citation

Tran, H.N.T.,McMahon, K.L.,Deuis, J.R.,Vetter, I.,Schroeder, C.I.
Structural and functional insights into the inhibition of human voltage-gated sodium channels by mu-conotoxin KIIIA disulfide isomers.
J.Biol.Chem., 298:101728-101728, 2022

PubMed Abstract: μ-Conotoxins are components of cone snail venom, well-known for their analgesic activity through potent inhibition of voltage-gated sodium channel (Na) subtypes, including Na1.7. These small, disulfide-rich peptides are typically stabilized by three disulfide bonds arranged in a 'native' CysI-CysIV, CysII-CysV, CysIII-CysVI pattern of disulfide connectivity. However, μ-conotoxin KIIIA, the smallest and most studied μ-conotoxin with inhibitory activity at Na1.7, forms two distinct disulfide bond isomers during thermodynamic oxidative folding, including Isomer 1 (CysI-CysV, CysII-CysIV, CysIII-CysVI) and Isomer 2 (CysI-CysVI, CysII-CysIV, CysIII-CysV), but not the native μ-conotoxin arrangement. To date, there has been no study on the structure and activity of KIIIA comprising the native μ-conotoxin disulfide bond arrangement. Here, we evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of the three isomers of KIIIA. Using a regioselective disulfide bond-forming strategy, we synthetically produced the three μ-conotoxin KIIIA isomers displaying distinct bioactivity and Na subtype selectivity across human Na channel subtypes 1.2, 1.4, and 1.7. We show that Isomer 1 inhibits Na subtypes with a rank order of potency of Na1.4 > 1.2 > 1.7 and Isomer 2 in the order of Na1.4≈1.2 > 1.7, while the native isomer inhibited Na1.4 > 1.7≈1.2. The three KIIIA isomers were further evaluated by NMR solution structure analysis and molecular docking with hNa1.2. Our study highlights the importance of investigating alternate disulfide isomers, as disulfide connectivity affects not only the overall structure of the peptides but also the potency and subtype selectivity of μ-conotoxins targeting therapeutically relevant Na subtypes.

PubMed: 35167877
DOI: 10.1016/j.jbc.2022.101728

Experimental method

SOLUTION NMR