4hhf | pdb_00004hhf
Crystal Structure of chemically synthesized scorpion alpha-toxin OD1
Structural highlights
Function[SCX1_ODODO] Alpha toxins bind voltage-independently at site-3 of sodium channels and inhibit the inactivation of the activated channels, thereby blocking neuronal transmission. Mammalian sodium channels Nav1.5/SCN2A (only at micromolar concentrations), Nav1.7/SCN9A (EC(50)=4.5 nM) and insect sodium channel para/tipE (EC(50)=80 nM) are affected by this toxin, whereas mammalian sodium channels Nav1.2/SCN2A, Nav1.3/SCN3A, and Nav1.8/SCN10A are unaffected by high concentrations.[1] [2] Publication Abstract from PubMedScorpion alpha-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 alpha-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 A) of synthetic OD1 showed the typical betaalphabetabeta alpha-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other alpha-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent alpha-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent beta-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 alpha-toxins with altered selectivity at Nav subtypes. Chemical Engineering and Structural and Pharmacological Characterization of the alpha-Scorpion Toxin OD1.,Durek T, Vetter I, Wang CI, Motin L, Knapp O, Adams DJ, Lewis RJ, Alewood PF ACS Chem Biol. 2013 Apr 3. PMID:23527544[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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