Mutagenesis of α-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors

Nicotinic acetylcholine receptors (nAChRs) are found throughout the mammalian body and have been studied extensively because of their implication in a myriad of diseases. α-Conotoxins (α-CTxs) are peptide neurotoxins found in the venom of marine snails of genus Conus. α-CTxs are potent and selective antagonists for a variety of nAChR isoforms. Over the past 40 years, α-CTxs have proven to be valuable molecular probes capable of differentiating between closely related nAChR subtypes and have contributed greatly to understanding the physiological role of nAChRs in the mammalian nervous system. Here, we review the amino acid composition and structure of several α-CTxs that selectively target nAChR isoforms and explore strategies and outcomes for introducing mutations in native α-CTxs to direct selectivity and enhance binding affinity for specific nAChRs. This review will focus on structure-activity relationship studies involving native α-CTxs that have been rationally mutated and molecular interactions that underlie binding between ligand and nAChR isoform.

• Publication year

  2019

• Venue

  Toxins

• Publication date

  2019-02-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/toxins11020113PMID 30781866PMCID 6409848
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype.

  2018cited by this paper
• Single Amino Acid Substitution in α-Conotoxin TxID Reveals a Specific α3β4 Nicotinic Acetylcholine Receptor Antagonist.

  2018influential reference
• Species specificity of rat and human &agr;7 nicotinic acetylcholine receptors towards different classes of peptide and protein antagonists

  2018influential reference
• Neuronal Nicotinic Acetylcholine Receptor Modulators from Cone Snails

  2018cited by this paper
• Cloning, Synthesis and Functional Characterization of a Novel α-Conotoxin Lt1.3

  2018influential reference
• The crystal structure of Ac-AChBP in complex with α-conotoxin LvIA reveals the mechanism of its selectivity towards different nAChR subtypes

  2017cited by this paper
• Insights into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment

  2017cited by this paper
• Nicotinic acetylcholine receptor inhibitors derived from snake and snail venoms.

  2017cited by this paper
• Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models

  2017influential reference
• Erratum to: The crystal structure of Ac-AChBP in complex with α-conotoxin LvIA reveals the mechanism of its selectivity towards different nAChR subtypes

  2017cited by this paper
• α-Conotoxins to explore the molecular, physiological and pathophysiological functions of neuronal nicotinic acetylcholine receptors.

  2017cited by this paper
• α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors.

  2017influential reference
• X-ray structure of the human α4β2 nicotinic receptor

  2016cited by this paper
• From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR

  2016cited by this paper
• Genetic Algorithm Managed Peptide Mutant Screening: Optimizing Peptide Ligands for Targeted Receptor Binding

  2016cited by this paper
• High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

  2016influential reference
• Allosteric modulation of nicotinic acetylcholine receptors.

  2015cited by this paper
• The Structural Features of α-Conotoxin Specifically Target Different Isoforms of Nicotinic Acetylcholine Receptors.

  2015cited by this paper
• Nicotinic ACh receptors as therapeutic targets in CNS disorders.

  2015cited by this paper
• α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity.

  2015cited by this paper
• Discovery of a Potent and Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist from an α-Conotoxin Synthetic Combinatorial Library

  2014influential reference
• Crystal structures of free and antagonist-bound states of human α9 nicotinic receptor extracellular domain

  2014cited by this paper
• Deciphering Fine Molecular Details of Proteins' Structure and Function with a Protein Surface Topography (PST) Method

  2014cited by this paper
• A novel α4/7‐conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors

  2014influential reference
• Acetylcholine Promotes Binding of α‐Conotoxin MII at α3β2 Nicotinic Acetylcholine Receptors

  2014cited by this paper
• Design and synthesis of α‐conotoxin GID analogues as selective α4β2 nicotinic acetylcholine receptor antagonists

  2014cited by this paper
• Discovery, synthesis, and structure-activity relationships of conotoxins.

  2014cited by this paper
• Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors.

  2014cited by this paper
• Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels*

  2013cited by this paper
• Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor.

  2013cited by this paper
• Characterization of a novel α-conotoxin TxID from Conus textile that potently blocks rat α3β4 nicotinic acetylcholine receptors.

  2013cited by this paper
• DockoMatic 2.0: High Throughput Inverse Virtual Screening and Homology Modeling

  2013cited by this paper
• Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with α4β2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes.

  2013cited by this paper
• pKa determination of histidine residues in α-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.

  2013cited by this paper
• Positional Scanning Mutagenesis of α-Conotoxin PeIA Identifies Critical Residues That Confer Potency and Selectivity for α6/α3β2β3 and α3β2 Nicotinic Acetylcholine Receptors*

  2013cited by this paper
• Crystal structure of a Cbtx–AChBP complex reveals essential interactions between snake α‐neurotoxins and nicotinic receptors

  2013cited by this paper
• IUPHAR-DB: updated database content and new features

  2012cited by this paper
• α-Conotoxin PeIA[S9H,V10A,E14N] Potently and Selectively Blocks α6β2β3 versus α6β4 Nicotinic Acetylcholine Receptors

  2012cited by this paper
• α6 nAChR subunit residues that confer α‐conotoxin BuIA selectivity

  2012cited by this paper
• Molecular docking study on the α3β2 neuronal nicotinic acetylcholine receptor complexed with α-conotoxin GIC.

  2012cited by this paper
• Characterization of a Novel α-Conotoxin from Conus textile That Selectively Targets α6/α3β2β3 Nicotinic Acetylcholine Receptors*

  2012cited by this paper
• Conus Venom Peptide Pharmacology

  2012cited by this paper
• Alternate states of proteins revealed by detailed energy landscape mapping.

  2011cited by this paper
• Real-Time PyMOL Visualization for Rosetta and PyRosetta

  2011cited by this paper
• Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist

  2011cited by this paper
• Crystal Structures of the Ligand Binding Domain of a Pentameric Alpha7 Nicotinic Receptor Chimera

  2011cited by this paper
• Structure-activity studies on alpha-conotoxins.

  2011cited by this paper
• α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

  2011cited by this paper
• Engineering of α‐conotoxin MII‐derived peptides with increased selectivity for native α6β2∗ nicotinic acetylcholine receptors

  2011cited by this paper
• Equilibrium conformational dynamics in an RNA tetraloop from massively parallel molecular dynamics

  2010cited by this paper
• Sub‐angstrom modeling of complexes between flexible peptides and globular proteins

  2010cited by this paper
• Synthetic α-Conotoxin Mutants as Probes for Studying Nicotinic Acetylcholine Receptors and in the Development of Novel Drug Leads

  2010cited by this paper
• α-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between α6ß4 and α6ß2 nicotinic acetylcholine receptors and blocks nicotine-stimulated norepinephrine release.

  2010cited by this paper
• Atypical α-Conotoxin LtIA from Conus litteratus Targets a Novel Microsite of the α3β2 Nicotinic Receptor*

  2010cited by this paper
• Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system

  2009cited by this paper
• Scanning Mutagenesis of α-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the α9α10 Nicotinic Acetylcholine Receptor*

  2009cited by this paper
• Rational Design of α-Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine Receptors

  2009cited by this paper
• Drug development from marine natural products

  2009cited by this paper
• Structural basis for alpha-conotoxin potency and selectivity.

  2009cited by this paper
• Remarkable inter- and intra-species complexity of conotoxins revealed by LC/MS.

  2009cited by this paper
• A Synthetic Combinatorial Strategy for Developing α-Conotoxin Analogs as Potent α7 Nicotinic Acetylcholine Receptor Antagonists*

  2009influential reference
• Rational design of alpha-conotoxin analogues targeting alpha7 nicotinic acetylcholine receptors: improved antagonistic activity by incorporation of proline derivatives.

  2009cited by this paper
• Inhibition of Neuronal Nicotinic Acetylcholine Receptor Subtypes by α-Conotoxin GID and Analogues*

  2009influential reference
• Recent advances in understanding the structure of nicotinic acetylcholine receptors

  2009cited by this paper
• Diversity of vertebrate nicotinic acetylcholine receptors.

  2009cited by this paper
• Amino Acid Residues That Confer High Selectivity of the α6 Nicotinic Acetylcholine Receptor Subunit to α-Conotoxin MII[S4A,E11A,L15A]*

  2008cited by this paper
• In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors.

  2008cited by this paper
• Macromolecular modeling with rosetta.

  2008cited by this paper
• GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation.

  2008cited by this paper
• α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking

  2008cited by this paper
• Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins?

  2007cited by this paper
• AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity

  2007cited by this paper
• Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist.

  2007cited by this paper
• Nicotinic receptors as CNS targets for Parkinson's disease.

  2007cited by this paper
• Crystal structure of the extracellular domain of the nicotinic acetylcholine receptor 1 subunit bound to alpha-bungarotoxin at 1.9 A resolution

  2007cited by this paper
• Are α9α10 Nicotinic Acetylcholine Receptors a Pain Target for α-Conotoxins?

  2007cited by this paper
• Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

  2007cited by this paper
• A semiempirical free energy force field with charge‐based desolvation

  2007cited by this paper
• Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery.

  2007cited by this paper
• Crystal structure of the extracellular domain of nAChR α1 bound to α-bungarotoxin at 1.94 Å resolution

  2007cited by this paper
• Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP.

  2006cited by this paper
• Fast and accurate algorithms for protein side-chain packing

  2006cited by this paper
• The Synthesis, Structural Characterization, and Receptor Specificity of the α-Conotoxin Vc1.1*

  2006cited by this paper
• Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors.

  2006cited by this paper
• Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

  2006cited by this paper
• Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant

  2005cited by this paper
• Crystal structure of a Cbtx–AChBP complex reveals essential interactions between snake α‐neurotoxins and nicotinic receptors

  2005cited by this paper
• GROMACS: Fast, flexible, and free

  2005cited by this paper
• Exploring the helix-coil transition via all-atom equilibrium ensemble simulations.

  2005cited by this paper
• Refined structure of the nicotinic acetylcholine receptor at 4A resolution.

  2005cited by this paper
• Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.

  2005cited by this paper
• Crystal Structure of Acetylcholine-binding Protein from Bulinus truncatus Reveals the Conserved Structural Scaffold and Sites of Variation in Nicotinic Acetylcholine Receptors*

  2005cited by this paper
• Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

  2005influential reference
• Conotoxins as research tools and drug leads.

  2005cited by this paper
• Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones.

  2005cited by this paper
• A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors.

  2005influential reference
• Alpha-conotoxin BuIA, a novel peptide from Conus bullatus, distinguishes among neuronal nicotinic acetylcholine receptors.

  2005cited by this paper
• α-Conotoxin BuIA, a Novel Peptide from Conus bullatus, Distinguishes among Neuronal Nicotinic Acetylcholine Receptors*

  2005cited by this paper
• A Novel α-Conotoxin, PeIA, Cloned from Conus pergrandis, Discriminates between Rat α9α10 and α7 Nicotinic Cholinergic Receptors*

  2005cited by this paper
• Crystal Structure of Acetylcholine-binding Protein (AChBP) from Aplysia californica in complex with an alpha-conotoxin PnIA variant

  2005cited by this paper

• Prediction of Specificity of α‑Conotoxins to Subtypes of Human Nicotinic Acetylcholine Receptors with Semi-supervised Machine Learning

  2025cites this paper
• Selective Inhibition of Rat α7 Nicotinic Acetylcholine Receptors by LvID, a Newly Characterized α4/7-Conotoxin from Conus lividus.

  2025cites this paper
• Advances in Biosensors for the Rapid Detection of Marine Biotoxins: Current Status and Future Perspectives

  2024cites this paper
• In Silico Conotoxin Studies: Progress and Prospects

  2024cites this paper
• Single Amino Acid Substitution in Loop1 Switches the Selectivity of α-Conotoxin RegIIA towards the α7 Nicotinic Acetylcholine Receptor

  2024cites this paper
• Diverse toxins exhibit a common binding mode to the nicotinic acetylcholine receptors

  2024cites this paper
• Bibliometric Review of the Literature on Cone Snail Peptide Toxins from 2000 to 2022

  2023cites this paper
• Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies.

  2023cites this paper
• Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors.

  2023cites this paper
• Historical Perspective of the Characterization of Conotoxins Targeting Voltage-Gated Sodium Channels

  2023cites this paper
• Characterisation of Elevenin-Vc1 from the Venom of Conus victoriae: A Structural Analogue of α-Conotoxins

  2023cites this paper
• Synthesis and characterization of αM-conotoxin SIIID, a reversible human α7 nicotinic acetylcholine receptor antagonist.

  2022cites this paper
• Characterization of an α 4/7-Conotoxin LvIF from Conus lividus That Selectively Blocks α3β2 Nicotinic Acetylcholine Receptor

  2021cites this paper
• Toxinology of Marine Venomous Snails

  2021cites this paper
• The 3/4- and 3/6-Subfamily Variants of α-Conotoxins GI and MI Exhibit Potent Inhibitory Activity against Muscular Nicotinic Acetylcholine Receptors

  2021cites this paper
• Marine-derived nicotinic receptor antagonist toxins: Pinnatoxins and alpha conotoxins

  2021cites this paper
• Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR

  2020cites this paper
• High Selectivity of an α-Conotoxin LvIA Analogue for α3β2 Nicotinic Acetylcholine Receptors Is Mediated by β2 Functionally Important Residues.

  2020cites this paper
• Rational Design of α-Conotoxin RegIIA Analogues Specifically Inhibiting the Human α3β2 Nicotinic Acetylcholine Receptor through Computational Scanning.

  2020cites this paper
• In silico modeling of the α7 nicotinic acetylcholine receptor: new pharmacological challenges associated with multiple modes of signaling.

  2020cites this paper
• Structural and Functional Analyses of Cone Snail Toxins

  2019cites this paper
• Ribbon α-Conotoxin KTM Exhibits Potent Inhibition of Nicotinic Acetylcholine Receptors

  2019cites this paper
• Qualitative Assay to Detect Dopamine Release by Ligand Action on Nicotinic Acetylcholine Receptors

  2019cites this paper
• Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi

  2019cites this paper
• PeIA-5466: A novel peptide antagonist containing non-natural amino acids that selectively targets α3β2 nicotinic acetylcholine receptors.

  2019cites this paper