1G1Z

NMR Solution Structures of delta-Conotoxin EVIA from Conus ermineus that Selectively Acts on Vertebrate Neuronal Na+ Channels, LEU12-PRO13 Cis isomer

Summary for 1G1Z

• Entry DOI: 10.2210/pdb1g1z/pdb
• Related: 1G1P
• Descriptor: CONOTOXIN EVIA (1 entity in total)
• Functional Keywords: three disulfide linkages, cis/trans isomerism of leu12-pro13 peptide bond, hydroxyproline, toxin
• Total number of polymer chains: 1
• Total formula weight: 3294.91

Authors

Volpon, L.,Lamthanh, H.,Le Gall, F.,Menez, A.,Lancelin, J.M. (deposition date: 2000-10-16, release date: 2000-11-01, Last modification date: 2022-02-23)

Primary citation

Volpon, L.,Lamthanh, H.,Barbier, J.,Gilles, N.,Lancelin, J.M.
NMR Solution Structures of delta-Conotoxin EVIA from Conus ermineus That Selectively Acts on Vertebrate Neuronal Na+ Channels.
J.Biol.Chem., 279:21356-21366, 2004

PubMed Abstract: Delta-conotoxin EVIA, from Conus ermineus, is a 32-residue polypeptide cross-linked by three disulfide bonds forming a four-loop framework. delta-Conotoxin EVIA is the first conotoxin known to inhibit sodium channel inactivation in neuronal membranes from amphibians and mammals (subtypes rNa(v)1.2a, rNa(v)1.3, and rNa(v)1.6), without affecting rat skeletal muscle (subtype rNa(v)1.4) and human cardiac muscle (subtype hNa(v)1.5) sodium channel (Barbier, J., Lamthanh, H., Le Gall, F., Favreau, P., Benoit, E., Chen, H., Gilles, N., Ilan, N., Heinemann, S. F., Gordon, D., Ménez, A., and Molgó, J. (2004) J. Biol. Chem. 279, 4680-4685). Its structure was solved by NMR and is characterized by a 1:1 cis/trans isomerism of the Leu(12)-Pro(13) peptide bond in slow exchange on the NMR time scale. The structure of both cis and trans isomers could be calculated separately. The isomerism occurs within a specific long disordered loop 2, including residues 11-19. These contribute to an important hydrophobic patch on the surface of the toxin. The rest of the structure matches the "inhibitor cystine-knot motif" of conotoxins from the "O superfamily" with a high structural order. To probe a possible functional role of the Leu(12)-Pro(13) cis/trans isomerism, a Pro(13) --> Ala delta-conotoxin EVIA was synthesized and shown to exist only as a trans isomer. P13A delta-conotoxin EVIA was estimated only two times less active than the wild-type EVIA in binding competition to rat brain synaptosomes and when injected intracerebroventricularly into mice.

PubMed: 14976206
DOI: 10.1074/jbc.M309594200

Experimental method

SOLUTION NMR