4HHF

Crystal Structure of chemically synthesized scorpion alpha-toxin OD1

Summary for 4HHF

• Entry DOI: 10.2210/pdb4hhf/pdb
• Descriptor: Alpha-toxin OD1, (4S)-2-METHYL-2,4-PENTANEDIOL (3 entities in total)
• Functional Keywords: 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
• Biological source: Odontobuthus doriae (Yellow Iranian scorpion)
• Cellular location: Secreted: P84646
• Total number of polymer chains: 1
• Total formula weight: 7575.71

Authors

Wang, C.I.A.,Lewis, R.J.,Alewood, P.F.,Durek, T. (deposition date: 2012-10-09, release date: 2013-04-24, Last modification date: 2024-10-16)

Primary citation

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

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)