α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement.
Summary (1 min read)
1. Introduction
- Conotoxins are disulfide-rich peptides from the venom of marine snails of the Conus genus.
- In the nervous system, they mediate the role of the neurotransmitter acetylcholine and are involved in rapid synaptic transmission.
- 25-27 The evidence that the nAChRs play a role in a number of different neuronal functions and disorders has given impetus to the search for drugs that selectively modulate different nAChR subtypes.
- 33,34 To date, the crystal structure of Vc1.1 bound-α9α10 nAChR remains unavailable, and computational modeling in combination with mutagenesis studies have been used as an effective method for understanding the structure-activity relationship.
2. Results and discussion
- Specific Vc1.1 side chains were minimally modified to validate the previously determined binding modes of Vc1.1 and to understand the structure-activity relationship of Vc1.1 with the α9α10 nAChR.
- The results disagree with their modeling studies in which two hydrogen bonds were identified between the hydroxyl group of Vc1.1 Y10 and the backbone H atom of α9 D119 and O atom of α9 N107 .
- The K, Dab and Dap residues all possess a positively charged amine group at the side chain terminus, whereas their potency is remarkably different suggesting that appropriate length of the side chain is essential for the formation of favourable electrostatic interaction with the proposed D169 and D166 in their model .
- The mutational effects of the [S4K, N9A] double mutation were not cumulative of the single mutations, since the double mutant could only select either the orientation of [S4K]Vc1.1 or [N9A]Vc1.1 upon binding to the receptor.
- The second generation [S4Dab, N9A]Vc1.1 and [S4Dab, N9W]Vc1.1 analogues were chemically synthesized, and their activity was determined at heterologously expressed hα9α10 nAChR.
3. Conclusions
- In summary, using previously built α9α10 nAChR model as guidance, the authors designed a library of Vc1.1 analogues by introducing residues with similar physicochemical properties to the wild-type residues in order to validate the accuracy of the model and investigated the structure-activity relationship of Vc1.1 with the hα9α10 nAChR at the atomic level.
- The authors findings suggest that Vc1.1 S4 forms hydrogen bonds with α9 D166 and D169, and introducing positively charged residues at this position can improve the potency.
- The P6 is nearby D119, and the introduced Hyp6 approaches D119 and forms a hydrogen bond.
- The side chain length and the number of negative charges are essential for residue at 10 position of Vc1.1.
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Cites background from "α-Conotoxin Vc1.1 Structure-Activit..."
...Indeed, a large number of subclassifications of receptors have been discovered using conopeptide probes [6], [10], [11], [12], [13]....
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References
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Additional excerpts
...24 References: (1) Olivera, B. M., Gray, W. R., Zeikus, R., McIntosh, J. M., Varga, J., Rivier, J., de Santos, V., and Cruz, L. J. (1985) Peptide neurotoxins from fish-hunting cone snails. Science (N.Y.) 230, 1338-1343. (2) Olivera, B. M., Rivier, J., Clark, C., Ramilo, C. A., Corpuz, G. P., Abogadie, F. C., Mena, E. E., Woodward, S. R., Hillyard, D. R., and Cruz, L. J. (1990) Diversity of Conus neuropeptides....
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...24 References: (1) Olivera, B. M., Gray, W. R., Zeikus, R., McIntosh, J. M., Varga, J., Rivier, J., de Santos, V., and Cruz, L. J. (1985) Peptide neurotoxins from fish-hunting cone snails. Science (N.Y.) 230, 1338-1343. (2) Olivera, B. M., Rivier, J., Clark, C., Ramilo, C. A., Corpuz, G. P., Abogadie, F. C., Mena, E. E., Woodward, S. R., Hillyard, D. R., and Cruz, L. J. (1990) Diversity of Conus neuropeptides. Science (N.Y.) 249, 257-263. (3) Terlau, H., and Olivera, B. M. (2004) Conus venoms: A rich source of novel ion channel-targeted peptides....
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...24 References: (1) Olivera, B. M., Gray, W. R., Zeikus, R., McIntosh, J. M., Varga, J., Rivier, J., de Santos, V., and Cruz, L. J. (1985) Peptide neurotoxins from fish-hunting cone snails....
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213 citations