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Anal Chem. 2018 Mar 6;90(5):3321-3327. doi: 10.1021/acs.analchem.7b04854. Epub 2018 Feb 8.

Conformational μ-Conotoxin PIIIA Isomers Revisited: Impact of Cysteine Pairing on Disulfide-Bond Assignment and Structure Elucidation.

Author information

1
Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , D-53121 Bonn , Germany.
2
Clemens Schöpf Institute of Organic Chemistry and Biochemistry , Darmstadt University of Technology , Alarich-Weiss-Strasse 4 , D-64287 Darmstadt , Germany.
3
MALDI Applications and Proteomics R&D , Bruker Daltonics GmbH , Fahrenheitstrasse 4 , D-28359 Bremen , Germany.
4
Leibniz Institute on Aging - Fritz Lipmann Institute , Beutenbergstrasse 11 , D-07745 Jena , Germany.
5
Eduard Zintl Institute of Inorganic and Physical Chemistry , Darmstadt University of Technology , Alarich-Weiss-Strasse 4 , D-64287 Darmstadt , Germany.

Abstract

Peptides and proteins carrying high numbers of cysteines can adopt various 3D structures depending on their disulfide connectivities. The unambiguous verification of such conformational isomers with more than two disulfide bonds is extremely challenging, and experimental strategies for their unequivocal structural analysis are largely lacking. We synthesized all 15 possible isomers of the 22mer conopeptide μ-PIIIA and applied 2D NMR spectroscopy and MS/MS for the elucidation of its structure. This study provides intriguing insights in how the disulfide connectivity alters the global fold of a toxin. We also show that analysis procedures involving comprehensive combinations of conventional methods are required for the unambiguous assignment of disulfides in cysteine-rich peptides and proteins and that standard compounds are crucially needed for the structural analysis of such complex molecules.

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