4HHF
Crystal Structure of chemically synthesized scorpion alpha-toxin OD1
4HHF の概要
エントリーDOI | 10.2210/pdb4hhf/pdb |
分子名称 | Alpha-toxin OD1, (4S)-2-METHYL-2,4-PENTANEDIOL (3 entities in total) |
機能のキーワード | scorpion long-chain alpha-toxin, gating modulator, voltage-gated sodium channels 1.4, 1.6, 1.7, inhibition of fast channel inactivation, c-terminally amidated, venom gland, toxin |
由来する生物種 | Odontobuthus doriae (Yellow Iranian scorpion) |
細胞内の位置 | Secreted: P84646 |
タンパク質・核酸の鎖数 | 1 |
化学式量合計 | 7575.71 |
構造登録者 | Wang, C.I.A.,Lewis, R.J.,Alewood, P.F.,Durek, T. (登録日: 2012-10-09, 公開日: 2013-04-24, 最終更新日: 2024-10-16) |
主引用文献 | Durek, T.,Vetter, I.,Wang, C.I.,Motin, L.,Knapp, O.,Adams, D.J.,Lewis, R.J.,Alewood, P.F. Chemical engineering and structural and pharmacological characterization of the alpha-scorpion toxin OD1. Acs Chem.Biol., 8:1215-1222, 2013 Cited by PubMed Abstract: Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure-function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other α-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent β-toxin activity at Nav1.4 and Nav1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Nav1.4 and Nav1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Nav1.7 over Nav1.6, while OD1 K11V was 5-fold more selective for Nav1.6 than Nav1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Nav subtypes. PubMed: 23527544DOI: 10.1021/cb400012k 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.8 Å) |
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