ArticleThe Journal of biological chemistry2013
Positional scanning mutagenesis of α-conotoxin PeIA identifies critical residues that confer potency and selectivity for α6/α3β2β3 and α3β2 nicotinic acetylcholine receptors.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Single Amino Acid Substitution in Loop1 Switches the Selectivity of α-Conotoxin RegIIA towards the α7 Nicotinic Acetylcholine Receptor.Marine drugs · 2024Article
- Computational Design of α-Conotoxins to Target Specific Nicotinic Acetylcholine Receptor Subtypes.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
- Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID.Marine drugs · 2023Article
- A Novel α4/7-Conotoxin QuIA Selectively Inhibits α3β2 and α6/α3β4 Nicotinic Acetylcholine Receptor Subtypes with High Efficacy.Marine drugs · 2022Article
- Cross Talk between α7 and α3β4 Nicotinic Receptors Prevents Their Desensitization in Human Chromaffin Cells.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications.Biomolecules · 2022Review
- Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA.Scientific reports · 2021Article
- Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor.Marine drugs · 2021Article
- Venom-Derived Neurotoxins Targeting Nicotinic Acetylcholine Receptors.Molecules (Basel, Switzerland) · 2021Review
- Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs.Journal of medicinal chemistry · 2021Article
- Unique Pharmacological Properties of α-Conotoxin OmIA at α7 nAChRs.Frontiers in pharmacology · 2021Article
- α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia.Toxins · 2020Review
- Expression of α3β2β4 nicotinic acetylcholine receptors by rat adrenal chromaffin cells determined using novel conopeptide antagonists.Journal of neurochemistry · 2020Article
- Effects of Cyclization on Activity and Stability of α-Conotoxin TxIB.Marine drugs · 2020Article
- Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins.Frontiers in neuroscience · 2020Review
- Identification of Crucial Residues in α-Conotoxin EI Inhibiting Muscle Nicotinic Acetylcholine Receptor.Toxins · 2019Article
- α-Conotoxin VnIB from Conus ventricosus is a potent and selective antagonist of α6β4* nicotinic acetylcholine receptors.Neuropharmacology · 2019Article
- PeIA-5466: A Novel Peptide Antagonist Containing Non-natural Amino Acids That Selectively Targets α3β2 Nicotinic Acetylcholine Receptors.Journal of medicinal chemistry · 2019Article
- d-Amino Acid Substitution of α-Conotoxin RgIA Identifies its Critical Residues and Improves the Enzymatic Stability.Marine drugs · 2019Article
- Mutagenesis of α-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors.Toxins · 2019Review
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Authors and funding
7 authors.
Funding
Abstract
The nicotinic acetylcholine receptor (nAChR) subtype α6β2* (the asterisk denotes the possible presence of additional subunits) has been identified as an important molecular target for the pharmacotherapy of Parkinson disease and nicotine dependence. The α6 subunit is closely related to the α3 subunit, and this presents a problem in designing ligands that discriminate between α6β2* and α3β2* nAChRs. We used positional scanning mutagenesis of α-conotoxin PeIA, which targets both α6β2* and α3β2*, in combination with mutagenesis of the α6 and α3 subunits, to gain molecular insights into the interaction of PeIA with heterologously expressed α6/α3β2β3 and α3β2 receptors. Mutagenesis of PeIA revealed that Asn(11) was located in an important position that interacts with the α6 and α3 subunits. Substitution of Asn(11) with a positively charged amino acid essentially abolished the activity of PeIA for α3β2 but not for α6/α3β2β3 receptors. These results were used to synthesize a PeIA analog that was >15,000-fold more potent on α6/α3β2β3 than α3β2 receptors. Analogs with an N11R substitution were then used to show a critical interaction between the 11th position of PeIA and Glu(152) of the α6 subunit and Lys(152) of the α3 subunit. The results of these studies provide molecular insights into designing ligands that selectively target α6β2* nAChRs.
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