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4HHF

Crystal Structure of chemically synthesized scorpion alpha-toxin OD1

4HHF の概要
エントリーDOI10.2210/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: 23527544
DOI: 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)
構造検証レポート
Validation report summary of 4hhf
検証レポート(詳細版)ダウンロードをダウンロード

238895

件を2025-07-16に公開中

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