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Publication Abstract from PubMed

In Naja kaouthia cobra venom, we have earlier discovered a covalent dimeric form of alpha-cobratoxin (alphaCT-alphaCT) with two intermolecular disulfides, but we could not determine their positions. Here, we report the alphaCT-alphaCT crystal structure at 1.94 A where intermolecular disulfides are identified between Cys(3) in one protomer and Cys(20) of the second, and vice versa. All remaining intramolecular disulfides, including the additional bridge between Cys(26) and Cys(30) in the central loops II, have the same positions as in monomeric alpha-cobratoxin. The three-finger fold is essentially preserved in each protomer, but the arrangement of the alphaCT-alphaCT dimer differs from those of noncovalent crystallographic dimers of three-finger toxins (TFT) or from the kappa-bungarotoxin solution structure. Selective reduction of Cys(26)-Cys(30) in one protomer does not affect the activity against the alpha7 nicotinic acetylcholine receptor (nAChR), whereas its reduction in both protomers almost prevents alpha7 nAChR recognition. On the contrary, reduction of one or both Cys(26)-Cys(30) disulfides in alphaCT-alphaCT considerably potentiates inhibition of the alpha3beta2 nAChR by the toxin. The heteromeric dimer of alpha-cobratoxin and cytotoxin has an activity similar to that of alphaCT-alphaCT against the alpha7 nAChR and is more active against alpha3beta2 nAChRs. Our results demonstrate that at least one Cys(26)-Cys(30) disulfide in covalent TFT dimers, similar to the monomeric TFTs, is essential for their recognition by alpha7 nAChR, although it is less important for interaction of covalent TFT dimers with the alpha3beta2 nAChR.

Dimeric alpha-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors.,Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI J Biol Chem. 2012 Feb 24;287(9):6725-34. Epub 2012 Jan 5. PMID:22223648^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.