scholarly journals Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-terminal Tail

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 141
Author(s):  
Julien Giribaldi ◽  
Yves Haufe ◽  
Edward R. J. Evans ◽  
David T. Wilson ◽  
Norelle L. Daly ◽  
...  
Keyword(s):  
Biological Activity ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Three Dimensional ◽  
Venom Gland ◽  
Dimensional Structure ◽  
Major Influence ◽  
Dominant Group ◽  
Marine Predators ◽  
Pharmacological Targets

Cone snails are venomous marine predators that rely on fast-acting venom to subdue their prey and defend against aggressors. The conotoxins produced in the venom gland are small disulfide-rich peptides with high affinity and selectivity for their pharmacological targets. A dominant group comprises α-conotoxins, targeting nicotinic acetylcholine receptors. Here, we report on the synthesis, structure determination and biological activity of a novel α-conotoxin, CIC, found in the predatory venom of the piscivorous species Conus catus and its truncated mutant Δ-CIC. CIC is a 4/7 α-conotoxin with an unusual extended N-terminal tail. High-resolution NMR spectroscopy shows a major influence of the N-terminal tail on the apparent rigidity of the three-dimensional structure of CIC compared to the more flexible Δ-CIC. Surprisingly, this effect on the structure does not alter the biological activity, since both peptides selectively inhibit α3β2 and α6/α3β2β3 nAChRs with almost identical sub- to low micromolar inhibition constants. Our results suggest that the N-terminal part of α-conotoxins can accommodate chemical modifications without affecting their pharmacology.

scholarly journals Ribbon α-Conotoxin KTM Exhibits Potent Inhibition of Nicotinic Acetylcholine Receptors

Marine Drugs ◽  
2019 ◽  
Vol 17 (12) ◽  
pp. 669
Author(s):  
Leanna A. Marquart ◽  
Matthew W. Turner ◽  
Lisa R. Warner ◽  
Matthew D. King ◽  
James R. Groome ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Nicotinic Acetylcholine ◽  
Amino Acid Peptide ◽  
Potent Inhibition ◽  
Helical Content ◽  
Distance Restraints ◽  
Native Fold

KTM is a 16 amino acid peptide with the sequence WCCSYPGCYWSSSKWC. Here, we present the nuclear magnetic resonance (NMR) structure and bioactivity of this rationally designed α-conotoxin (α-CTx) that demonstrates potent inhibition of rat α3β2-nicotinic acetylcholine receptors (rα3β2-nAChRs). Two bioassays were used to test the efficacy of KTM. First, a qualitative PC12 cell-based assay confirmed that KTM acts as a nAChR antagonist. Second, bioactivity evaluation by two-electrode voltage clamp electrophysiology was used to measure the inhibition of rα3β2-nAChRs by KTM (IC50 = 0.19 ± 0.02 nM), and inhibition of the same nAChR isoform by α-CTx MII (IC50 = 0.35 ± 0.8 nM). The three-dimensional structure of KTM was determined by NMR spectroscopy, and the final set of 20 structures derived from 32 distance restraints, four dihedral angle constraints, and two disulfide bond constraints overlapped with a mean global backbone root-mean-square deviation (RMSD) of 1.7 ± 0.5 Å. The structure of KTM did not adopt the disulfide fold of α-CTx MII for which it was designed, but instead adopted a flexible ribbon backbone and disulfide connectivity of C2–C16 and C3–C8 with an estimated 12.5% α-helical content. In contrast, α-CTx MII, which has a native fold of C2–C8 and C3–C16, has an estimated 38.1% α-helical secondary structure. KTM is the first reported instance of a Framework I (CC-C-C) α-CTx with ribbon connectivity to display sub-nanomolar inhibitory potency of rα3β2-nAChR subtypes.

scholarly journals Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1016 ◽  
Author(s):  
Federica Bono ◽  
Veronica Mutti ◽  
Chiara Fiorentini ◽  
Cristina Missale
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuronal Development ◽  
G Protein Coupled Receptors ◽  
D3 Receptor ◽  
Pharmacological Targets ◽  
Receptor Heteromers ◽  
Dopamine D3 ◽  
Functional Features ◽  
G Protein Coupled

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design.

scholarly journals Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha3beta2 nicotinic acetylcholine receptors

2004 ◽  
Vol 380 (2) ◽  
pp. 347-352 ◽  
Author(s):  
Seung-Wook CHI ◽  
Do-Hyoung KIM ◽  
Baldomero M. OLIVERA ◽  
J. Michael McINTOSH ◽  
Kyou-Hoon HAN
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Solution Structure ◽  
Heavy Atom ◽  
Three Dimensional ◽  
Cone Snail ◽  
Dimensional Solution ◽  
Nicotinic Acetylcholine ◽  
Binding Characteristics ◽  
Molecular Features

α-Conotoxin GIC is a 16-residue peptide isolated from the venom of the cone snail Conus geographus. α-Conotoxin GIC potently blocks the α3β2 subtype of human nicotinic acetylcholine receptor, showing a high selectivity for neuronal versus muscle subtype [McIntosh, Dowell, Watkins, Garrett, Yoshikami, and Olivera (2002) J. Biol. Chem. 277, 33610–33615]. We have now determined the three-dimensional solution structure of α-conotoxin GIC by NMR spectroscopy. The structure of α-conotoxin GIC is well defined with backbone and heavy atom root mean square deviations (residues 2–16) of 0.53 Å and 0.96 Å respectively. Structure and surface comparison of α-conotoxin GIC with the other α4/7 subfamily conotoxins reveals unique structural aspects of α-conotoxin GIC. In particular, the structural comparison between α-conotoxins GIC and MII indicates molecular features that may confer their similar receptor specificity profile, as well as those that provide the unique binding characteristics of α-conotoxin GIC.

Synthesis and biological activity of a novel class nicotinic acetylcholine receptors (nAChRs) ligands structurally related to anatoxin-a

2011 ◽  
Vol 21 (18) ◽  
pp. 5423-5427 ◽  
Author(s):  
Daniele Simoni ◽  
Riccardo Rondanin ◽  
Paolo Marchetti ◽  
Cinzia Rullo ◽  
Riccardo Baruchello ◽  
...  
Keyword(s):  
Biological Activity ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

scholarly journals Pursuing High-Resolution Structures of Nicotinic Acetylcholine Receptors: Lessons Learned from Five Decades

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5753
Author(s):  
Manuel Delgado-Vélez ◽  
Orestes Quesada ◽  
Juan C. Villalobos-Santos ◽  
Rafael Maldonado-Hernández ◽  
Guillermo Asmar-Rovira ◽  
...  
Keyword(s):  
High Resolution ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Lessons Learned ◽  
Nicotinic Acetylcholine ◽  
Disease States ◽  
Pharmacological Targets ◽  
Therapeutic Value ◽  
Effective Drugs

Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their therapeutic value has been limited by the absence of high-resolution structures that allow for the design of more specific and effective drugs. This article offers a comprehensive review of five decades of research pursuing high-resolution structures of nAChRs. We provide a historical perspective, from initial structural studies to the most recent X-ray and cryogenic electron microscopy (Cryo-EM) nAChR structures. We also discuss the most relevant structural features that emerged from these studies, as well as perspectives in the field.

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