7sav | pdb_00007sav
Native mu-conotoxin KIIIA isomer
Structural highlights
FunctionCM3A_CONKI Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits).[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedmu-Conotoxins are components of cone snail venom, well-known for their analgesic activity through potent inhibition of voltage-gated sodium channel (NaV) subtypes, including NaV1.7. 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, mu-conotoxin KIIIA, the smallest and most studied mu-conotoxin with inhibitory activity at NaV1.7, 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 mu-conotoxin arrangement. To date, there has been no study on the structure and activity of KIIIA comprising the native mu-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 mu-conotoxin KIIIA isomers displaying distinct bioactivity and NaV subtype selectivity across human NaV channel subtypes 1.2, 1.4, and 1.7. We show that Isomer 1 inhibits NaV subtypes with a rank order of potency of NaV1.4 > 1.2 > 1.7 and Isomer 2 in the order of NaV1.4 approximately 1.2 > 1.7, while the native isomer inhibited NaV1.4 > 1.7 approximately 1.2. The three KIIIA isomers were further evaluated by NMR solution structure analysis and molecular docking with hNaV1.2. 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 mu-conotoxins targeting therapeutically relevant NaV subtypes. Structural and functional insights into the inhibition of human voltage-gated sodium channels by mu-conotoxin KIIIA disulfide isomers.,Tran HNT, McMahon KL, Deuis JR, Vetter I, Schroeder CI J Biol Chem. 2022 Mar;298(3):101728. doi: 10.1016/j.jbc.2022.101728. Epub 2022, Feb 12. PMID:35167877[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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