Snake Venoms by Hidetoshi Inagaki Carl-Wilhelm Vogel Ashis K. Mukherjee & Tarek R. Rahmy

Author:Hidetoshi Inagaki, Carl-Wilhelm Vogel, Ashis K. Mukherjee & Tarek R. Rahmy
Language: eng
Format: epub
Publisher: Springer Netherlands, Dordrecht

Reconciling the Structural Data of the Different α-Neurotoxin: Receptor Complexes

There are differences in the conclusions arising from the major studies that examined complexes formed between 3Fα-NTxs and short cognate peptides of the nAChR binding site (Zeng et al. 2001; Moise et al. 2002a), with the α1-subunit of the nAChR (Dellisanti et al. 2007), with the AChBP (Bourne et al. 2005), and with a AChBP-α7 nAChR chimera (Huang et al. 2013). These differences can be attributed to a multitude of factors, including limitations in resolution (4.2 Å) of the α-cobratoxin-AChBP complex structure (Bourne et al. 2005), difficulty in extrapolating information gleaned from short peptide segments to the intact nAChR (Zeng et al. 2001; Moise et al. 2002b), and absence of the complementary subunit in the formation of the complex in the case of the α-bungarotoxin – α1 subunit of the nAChR (Dellisanti et al. 2007). Nonetheless, all these studies agreed on the critical points of toxin-receptor interactions, which have also largely been substantiated by early mutational analysis. Importantly, the role of critical aromatic amino acids (e.g., Tyr184, Tyr190) as well as residues that are their direct neighbors, at the interface of the nAChR ligand-binding site, has been verified in the binding of 3Fα-NTxs. In particular, the role of loop C from the α1 subunit as the primary element essential for binding 3Fα-NTxs has been established. A multi-point attachment of the 3Fα-NTx to the receptor has also been observed, with the 3Fα-NTx binding perpendicularly to the receptor axis. The primary interaction of the toxin occurred via the tip of loop II, with Arg33/Arg36 playing the most crucial role, while loop I and the carboxy-terminal tail also contributed to contacts with the receptor surface. Significant flexibility of the carboxy-terminal tail and loop I as well as flexibility and conformational changes of the tip of loop II were also noted, which is proposed to have functional ramifications, allowing for dynamic interactions with previously inaccessible parts of the toxin and receptor.

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