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Journal Article•DOI•

α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement.

Xin Chu1, Han-Shen Tae2, Qingliang Xu1, Tao Jiang1, David J. Adams2, Rilei Yu1 •
Chinese Ministry of Education1, Illawarra Health & Medical Research Institute2
16 Oct 2019-ACS Chemical Neuroscience (ACS Chem Neurosci)-Vol. 10, Iss: 10, pp 4328-4336
TL;DR: The results suggest that the hydroxyl group of Vc1.1 Y10 forms hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required, whereas Vc2.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of V c1.
Abstract: α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1-bound α9α10 nAChR remains unavailable; thus, understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required. However, Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81, respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second-generation mutants of Vc1.1 [S4 Dab, N9A] and [S4 Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4 Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.

Summary (1 min read)

Jump to: [1. Introduction] – [2. Results and discussion] and [3. Conclusions]

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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1
α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10
Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain
Replacement
Xin Chu,
1,2ǂ
Han-Shen Tae,
3ǂ*
Qingliang Xu,
1,2
Tao Jiang,
1,2
David J. Adams,
3
and Rilei Yu
1,2,4*
1
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of
Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao
266003, China
2
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for
Marine Science and Technology, Qingdao 266003, China
3
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong,
Wollongong, New South Wales 2522, Australia
4
Innovation Center for Marine Drug Screening & Evaluation, Qingdao National
Laboratory for Marine Science and Technology, Qingdao 266003, China
*
Corresponding authors: hstae@uow.edu.au or ryu@ouc.edu.cn
ǂ
Both authors contributed equally to this manuscript.
2
ABSTRACT
α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10
subtype and has the potential to treat neuropathic chronic pain. To date, the crystal
structure of Vc1.1 bound-α9α10 nAChR remains unavailable, thus understanding the
structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging.
In this study, the Vc1.1 side chains were minimally modified to avoid introducing
large local conformation perturbation to the interactions between Vc1.1 and α9α10
nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen
bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required,
whereas Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue
at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl
group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81 respectively,
whereas introducing an extra carboxyl group at this position significantly decreases
the potency of Vc1.1. Second generation mutants of Vc1.1 [S4Dab, N9A] and [S4Dab,
N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of
Vc1.1. The [S4Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not
cumulative but are coupled with each other. Overall, our findings provide valuable
insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and
will contribute to further development of more potent and specific Vc1.1 analogues.
KEYWORDS: α-Conotoxin, nicotinic acetylcholine receptor; structure-activity
relationship; unnatural amino acids; molecular dynamics simulations; mutagenesis
3
1. Introduction
Conotoxins are disulfide-rich peptides from the venom of marine snails of the
Conus genus.
1-3
The conopeptides range from 10 to 40 amino acids in length and have
a compact structure stabilized by several disulfide bonds.
4
Compared with other
natural peptide toxins, conotoxins have considerable advantages such as relatively
small molecular mass, structural stability, high selectivity, potency, and easy
synthesis.
5-9
α-Conotoxins were one of the earliest discovered conotoxins, usually composed
of 12 to 30 amino acid residues,
10
and can specifically target nicotinic acetylcholine
receptors (nAChRs).
11
Several α-conotoxins have shown promising therapeutic
potential
12
with a most prominent example being α-conotoxin Vc1.1 (Figure 1A).
13
Vc1.1 is a 16 amino acid, disulfide-bonded peptide identified from the venom of C.
victoria
14
and potently inhibits the α9α10 nAChR.
15-17
nAChRs are pentameric ligand-gated ion channels consisting of an extracellular
domain, a transmembrane domain and an intracellular domain and are expressed in
the central and peripheral nervous systems and non-neuronal cells.
18,19
The conotoxin
binding site is located at the extracellular domain contributed by the principal (+) and
complementary (−) components of two adjacent subunits (α1-α10, β1-β4, γ, δ or ε).
20
In the nervous system, they mediate the role of the neurotransmitter acetylcholine and
are involved in rapid synaptic transmission.
21-23
The non-neuronal functions of
nAChRs include cellular proliferation and regulation of the immune system. There are
many different nAChR subtypes with preferential distribution in the nervous system,
Citations
More filters
Journal Article•DOI•
Medicinal chemistry, pharmacology, and therapeutic potential of α-conotoxins antagonizing the α9α10 nicotinic acetylcholine receptor.

[...]

Xiao Li1, Han-Shen Tae2, Yanyan Chu1, Tao Jiang1, David J. Adams2, Rilei Yu1 •
Chinese Ministry of Education1, Illawarra Health & Medical Research Institute2
01 Jun 2021-Pharmacology & Therapeutics
TL;DR: The structure and function of the α9α10 nAChR are highlighted and studies of α-conotoxins targeting it are reviewed, including their three-dimensional structures, structure optimization strategies, and binding modes at the α 9α10nA chR, as well as their therapeutic potential.

22 citations

Journal Article•DOI•
α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

[...]

Adam C. Kennedy1, Alessia Belgi1, Benjamin W. Husselbee1, David Spanswick2, David Spanswick3, David Spanswick4, Raymond S. Norton5, Andrea J. Robinson1 •
Monash University, Clayton campus1, Coventry Health Care2, University of Warwick3, Discovery Institute4, Monash University5
06 Aug 2020-Toxins
TL;DR: This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels.
Abstract: Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.

20 citations

Journal Article•DOI•
Mechanism of Action and Structure-Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor.

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Jiazhen Liang, Han-Shen Tae, Zitong Zhao, Xiao Li, Jinghui Zhang, Shen Chen, Tao Jiang, David H. Adams, Rilei Yu 
22 Sep 2022-Journal of Medicinal Chemistry
TL;DR: A formerly defined rat α7 nAChR targeting α-CTx Mr1.1 was chemically synthesized and displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.
Abstract: α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC50) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC50 of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

7 citations

Proceedings Article•DOI•
Alpha-family of Conotoxins: An Analysis of Structural Determinants

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Marineil C. Gomez1, Alisha Marcelle C. Aquino1, Andrea R. Matira1, Riggs Anton D. Alvarico1, Reincess E. Valbuena1, Lemmuel L. Tayo1 •
Mapúa Institute of Technology1
17 Oct 2019
TL;DR: The topological landscape of the conopeptides were influenced by the Cα backbone and the nature of the intervening amino acid, and are predominantly electron-poor regions, allowing them to act as Lewis acids, and may play a role in their ability to interact with ACh receptors.
Abstract: Conopeptides are small, disulfide-rich polypeptides that have great potential as sources of possible drug candidates due to their activity against membrane receptors and ion channels. A challenge to the faster high-throughput in silico screening of these potential drug candidates is their diversity in structure and relatively low sequence similarity despite similar functions. In this study, the conopeptides of the α-pharmacological family is studied based on their Cα backbone, surface topology and sequence analysis. Structural alignment using FATCAT shows good alignment of the conopeptides based on their RMSD values. The main factor contributing to the homology of their structures is not only the Cys (Cys) framework forming the disulfide bridges but also the number of intervening amino acids between the Cys residues and the length of the polypeptide. The topological landscape of the conopeptides were influenced by the Cα backbone and the nature of the intervening amino acid, and are predominantly electron-poor regions, allowing them to act as Lewis acids. This may play a role in their ability to interact with ACh receptors.

5 citations

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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Journal Article•DOI•
Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

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Igor E. Kasheverov, Denis S. Kudryavtsev, Irina V. Shelukhina, G. M. Nikolaev, Yuri N. Utkin, Victor I. Tsetlin 
23 Jan 2022-Biomolecules
TL;DR: In this review, the purpose of the review is to briefly show what different compounds of marine origin, from low molecular weight ones to peptides and proteins, offer for understanding the structure and mechanism of action of nicotinic acetylcholine receptors (nAChRs) and for finding novel drugs to combat the diseases where nA ChRs may be involved.
Abstract: The purpose of our review is to briefly show what different compounds of marine origin, from low molecular weight ones to peptides and proteins, offer for understanding the structure and mechanism of action of nicotinic acetylcholine receptors (nAChRs) and for finding novel drugs to combat the diseases where nAChRs may be involved. The importance of the mentioned classes of ligands has changed with time; a protein from the marine snake venom was the first excellent tool to characterize the muscle-type nAChRs from the electric ray, while at present, muscle and α7 receptors are labeled with the radioactive or fluorescent derivatives prepared from α-bungarotoxin isolated from the many-banded krait. The most sophisticated instruments to distinguish muscle from neuronal nAChRs, and especially distinct subtypes within the latter, are α-conotoxins. Such information is crucial for fundamental studies on the nAChR revealing the properties of their orthosteric and allosteric binding sites and mechanisms of the channel opening and closure. Similar data are provided by low-molecular weight compounds of marine origin, but here the main purpose is drug design. In our review we tried to show what has been obtained in the last decade when the listed classes of compounds were used in the nAChR research, applying computer modeling, synthetic analogues and receptor mutants, X-ray and electron-microscopy analyses of complexes with the nAChRs, and their models which are acetylcholine-binding proteins and heterologously-expressed ligand-binding domains.

5 citations

References
More filters
Journal Article•DOI•
Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System

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John A. Dani1, Daniel Bertrand•
Baylor College of Medicine1
08 Jan 2007-Annual Review of Pharmacology and Toxicology
TL;DR: Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics.
Abstract: Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's diseas...

1,119 citations

Journal Article•DOI•
Conus venoms: a rich source of novel ion channel-targeted peptides.

[...]

Heinrich Terlau1, Baldomero M. Olivera•
Max Planck Society1
01 Jan 2004-Physiological Reviews
TL;DR: This review focuses on the targeting specificity of conotoxins and their differential binding to different states of an ion channel.
Abstract: Terlau, Heinrich, and Baldomero M. Olivera. Conus Venoms: A Rich Source of Novel Ion Channel-Targeted Peptides. Physiol Rev 84: 41–68, 2004; 10.1152/physrev.00020.2003.—The cone snails (genus Conus...

890 citations

Journal Article•DOI•
The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building

[...]

François-Yves Dupradeau1, Adrien Pigache1, Thomas Zaffran1, Corentin Savineau1, Rodolphe Lelong1, Nicolas Grivel1, Dimitri Lelong1, Wilfried Rosanski1, Piotr Cieplak2 •
University of Picardie Jules Verne1, Sanford-Burnham Institute for Medical Research2
06 Jul 2010-Physical Chemistry Chemical Physics
TL;DR: These tools perform charge derivation in an automatic and straightforward way for non-polarizable charge models and incorporates charges into a force field library, readily usable in molecular dynamics computer packages.
Abstract: Deriving atomic charges and building a force field library for a new molecule are key steps when developing a force field required for conducting structural and energy-based analysis using molecular mechanics. Derivation of popular RESP charges for a set of residues is a complex and error prone procedure because it depends on numerous input parameters. To overcome these problems, the R.E.D. Tools (RESP and ESP charge Derive, http://q4md-forcefieldtools.org/RED/) have been developed to perform charge derivation in an automatic and straightforward way. The R.E.D. program handles chemical elements up to bromine in the periodic table. It interfaces different quantum mechanical programs employed for geometry optimization and computing molecular electrostatic potential(s), and performs charge fitting using the RESP program. By defining tight optimization criteria and by controlling the molecular orientation of each optimized geometry, charge values are reproduced at any computer platform with an accuracy of 0.0001 e. The charges can be fitted using multiple conformations, making them suitable for molecular dynamics simulations. R.E.D. allows also for defining charge constraints during multiple molecule charge fitting, which are used to derive charges for molecular fragments. Finally, R.E.D. incorporates charges into a force field library, readily usable in molecular dynamics computer packages. For complex cases, such as a set of homologous molecules belonging to a common family, an entire force field topology database is generated. Currently, the atomic charges and force field libraries have been developed for more than fifty model systems and stored in the RESP ESP charge DDataBase. Selected results related to non-polarizable charge models are presented and discussed.

775 citations

Journal Article•DOI•
Peptide neurotoxins from fish-hunting cone snails

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Baldomero M. Olivera, William R. Gray1, R Zeikus1, J M McIntosh, J Varga2, Jean Rivier2, V de Santos3, Lourdes J. Cruz3 •
University of Utah1, Salk Institute for Biological Studies2, University of the Philippines3
20 Dec 1985-Science
TL;DR: Five new omega-conotoxins that block presynaptic calcium channels are described, and the fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive.
Abstract: To paralyze their more agile prey, the venomous fish-hunting cone snails (Conus) have developed a potent biochemical strategy. They produce several classes of toxic peptides (conotoxins) that attack a series of successive physiological targets in the neuromuscular system of the fish. The peptides include presynaptic omega-conotoxins that prevent the voltage-activated entry of calcium into the nerve terminal and release of acetylcholine, postsynaptic alpha-conotoxins that inhibit the acetylcholine receptor, and muscle sodium channel inhibitors, the mu-conotoxins, which directly abolish muscle action potentials. These distinct peptide toxins share several common features: they are relatively small (13 to 29 amino acids), are highly cross-linked by disulfide bonds, and strongly basic. The fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive. Five new omega-conotoxins that block presynaptic calcium channels are described. They vary in their activity against different vertebrate classes, and also in their actions against different synapses from the same animal. There are susceptible forms of the target molecule in peripheral synapses of fish and amphibians, but those of mice are resistant. However, the mammalian central nervous system is clearly affected, and these toxins are thus of potential significance for investigating the presynaptic calcium channels.

715 citations

Journal Article•DOI•
α10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells

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Ana Belén Elgoyhen1, Douglas E. Vetter2, Eleonora Katz1, Carla V. Rothlin1, Stephen F. Heinemann2, Jim Boulter3 •
University of Buenos Aires1, Salk Institute for Biological Studies2, University of California, Los Angeles3
13 Mar 2001-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: The cloning and characterization of rat α10 are reported, a previously unidentified member of the nicotinic acetylcholine receptor (nAChR) subunit gene family, and data suggest that efferent modulation of hair cell function occurs, at least in part, through heteromeric nAChRs assembled from both α9 and α10 subunits.
Abstract: We report the cloning and characterization of rat α10, a previously unidentified member of the nicotinic acetylcholine receptor (nAChR) subunit gene family. The protein encoded by the α10 nAChR subunit gene is most similar to the rat α9 nAChR, and both α9 and α10 subunit genes are transcribed in adult rat mechanosensory hair cells. Injection of Xenopus laevis oocytes with α10 cRNA alone or in pairwise combinations with either α2-α6 or β2-β4 subunit cRNAs yielded no detectable ACh-gated currents. However, coinjection of α9 and α10 cRNAs resulted in the appearance of an unusual nAChR subtype. Compared with homomeric α9 channels, the α9α10 nAChR subtype displays faster and more extensive agonist-mediated desensitization, a distinct current–voltage relationship, and a biphasic response to changes in extracellular Ca2+ ions. The pharmacological profiles of homomeric α9 and heteromeric α9α10 nAChRs are essentially indistinguishable and closely resemble those reported for endogenous cholinergic eceptors found in vertebrate hair cells. Our data suggest that efferent modulation of hair cell function occurs, at least in part, through heteromeric nAChRs assembled from both α9 and α10 subunits.

662 citations

Related Papers (5)
Scanning Mutagenesis of α-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the α9α10 Nicotinic Acetylcholine Receptor

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24 Jul 2009-Journal of Biological Chemistry
Reena Halai, Richard J. Clark, Simon T. Nevin, Jonas E. Jensen, David J. Adams, David J. Craik 
Molecular determinants conferring the stoichiometric-dependent activity of α-conotoxins at the human α9α10 nicotinic acetylcholine receptor subtype

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07 May 2018-Journal of Medicinal Chemistry
Rilei Yu, Han-Shen Tae, Nargis Tabassum, Juan Shi, Tao Jiang, David J. Adams 
Presence of multiple binding sites on α9α10 nAChR receptors alludes to stoichiometric-dependent action of the α-conotoxin, Vc1.1.

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01 May 2014-Biochemical Pharmacology
Dinesh C. Indurthi, Elena Pera, Hye Lim Kim, Cindy Chu, Malcolm D. McLeod, J. Michael McIntosh, J. Michael McIntosh, Nathan L. Absalom, Mary Chebib 
Structure-Activity Studies Reveal the Molecular Basis for GABAB-Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α-Conotoxin Vc1.1.

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10 May 2018-ACS Chemical Biology
Mahsa Sadeghi, Bodil B. Carstens, Brid P Callaghan, James T. Daniel, Han-Shen Tae, Tracey A. O'Donnell, Joel Castro, Stuart M. Brierley, David J. Adams, David J. Craik, Richard J. Clark 
Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors.

[...]

01 Oct 2006-FEBS Journal
Igor E. Kasheverov, Maxim N. Zhmak, Catherine A. Vulfius, Elena V. Gorbacheva, Dmitry Y. Mordvintsev, Yuri N. Utkin, René van Elk, August B. Smit, Victor I. Tsetlin 
Frequently Asked Questions (1)
Q1. What are the contributions in "Α-conotoxin vc1.1 structure-activity relationship at the human α9α10 nicotinic acetylcholine receptor investigated by minimal side chain replacement" ?

In this paper, the authors proposed the α10 ( + ) -α9 ( − ) interface as the favorable binding site of Vc1.1 at the ( α9 ) 2 ( α10 ) 3 nAChR.