4aea

Dimeric alpha-cobratoxin X-ray structure: Localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors

spinqualitylabelsall models 4aea, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4aea is a 2 chain structure with sequence from Naja kaouthia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GLY, MPD Related: 1lxh, 1lxg, 1ctx Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NXL1_NAJKA] The monomeric form binds with high affinity to muscular, Torpedo (muscle-type), and neuronal alpha-7 nicotinic acetylcholine receptors (nAChR). Has no effect on alpha-3/beta-2 nAChR. Causes paralysis by preventing acetylcholine binding to the nAChR. Does not show any blockade of the nicotine-evoked release of dopamine and does not affect ACh release. In mice lung cancer, causes reduction of tumor growth. The homodimeric form binds with low affinity to Torpedo (muscle-type) and alpha-7 nAChRs, whereas it acquires the capacity to block alpha-3/beta-2 nAChRs. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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