Alpha-family of Conotoxins: An Analysis of Structural Determinants
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.
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TL;DR: In this paper, the authors employ a proteogenomic approach to maximize conopeptide identification from the injected venom of Conus purpurascens, which reveals two distinct venom profiles with different synergistic interactions to effectively target neural pathways aimed to immobilize prey.
5 citations
01 Jan 2015
TL;DR: A comprehensive overview of the distribution of cone shells and focus on the molecular approach in documenting their taxonomy and diversity with special reference to geographic distribution of Indian cone snails, structure and properties of conopeptide and their pharmacological targets and future directions is provided.
Abstract: The evolutionarily unique and ecologically diverse family Conidae presents fundamental opportunities for marine pharmacology research and drug discovery.The focus of this investigation is to summarize the worldwide distribution of Conus and their species diversity with special reference to the Indian coast.In addition,this study will contribute to understanding the structural properties of conotoxin and therapeutic application of Conus venom peptides.Cone snails can inject a mix of various conotoxins and these venoms are their major weapon for prey capture,and may also have other biological purposes,and some of these conotoxins fatal to humans.Conns venoms contain a remarkable diversity of pharmacologically active small peptides;their targets are an iron channel and receptors in the neuromuscular system.Interspecific divergence is pronounced in venom peptide genes,which is generally attributed to their species specific biotic interactions.There is a notable interspecific divergence observed in venom peptide genes,which can be justified as of biotic interactions that stipulate species peculiar habitat and ecology of cone snails.There are several conopeptides used in clinical trials and one peptide(Ziconotide) has received FDA approval for treatment of pain.This perspective provides a comprehensive overview of the distribution of cone shells and focus on the molecular approach in documenting their taxonomy and diversity with special reference to geographic distribution of Indian cone snails,structure and properties of conopeptide and their pharmacological targets and future directions.
5 citations
TL;DR: In this article , the authors conducted a two-phase study that investigated conotoxin evolution in terms of divergence, followed by structural analysis to determine the relevant structural elements that account for conotoxins' superior specificity.
Abstract: Simple Summary Conotoxins are small, structured components found in the venom of predatory cone snails. They were proven to be valuable probes and models for drug discovery and protein evolution studies. Conotoxins present an opportunity to study protein divergence and discover potential human therapeutic landscapes. Although there is considerable literature on conotoxin evolution and activity, what pushed conotoxin divergence remains unclear. Hence, in this paper, we conducted a two-phase study that investigated conotoxin evolution in terms of divergence, followed by structural analysis to determine the relevant structural elements. By understanding the evolution of conotoxins, we identified patterns that account for their superior specificity. The results revealed similarities based on the cone snail’s diet preference. The structural elements are in synch with their target prey preference as if cone snails evolved to fine-tune their conopeptide armory to respond to evolutionary pressures by producing conotoxins selective for their prey of choice. We identified several structural elements that account for this specificity. Conservation patterns are observed within diet subgroups but are divergent from other groups. Abstract Predatory cone snails (Conus) developed a sophisticated neuropharmacological mechanism to capture prey, escape against other predators, and deter competitors. Their venom’s remarkable specificity for various ion channels and receptors is an evolutionary feat attributable to the venom’s variety of peptide components (conotoxins). However, what caused conotoxin divergence remains unclear and may be related to the role of prey shift. Principal component analysis revealed clustering events within diet subgroups indicating peptide sequence similarity patterns based on the prey they subdue. Molecular analyses using multiple sequence alignment and structural element analysis were conducted to observe the events at the molecular level that caused the subgrouping. Three distinct subgroups were identified. Results showed homologous regions and conserved residues within diet subgroups but divergent between other groups. We specified that these structural elements caused subgrouping in alpha conotoxins that may play a role in function specificity. In each diet subgroup, amino acid character, length of intervening amino acids between cysteine residues, and polypeptide length influenced subgrouping. This study provides molecular insights into the role of prey shift, specifically diet preference, in conotoxin divergence.
1 citations
13 May 2022
TL;DR: PCA clustering, node grouping, and feature extraction suggest the increasing role of dietary preference, providing insights on the driving force that pushed conotoxins to diverge and diversify.
Abstract: Conotoxins are fast-evolving and highly diverse small, structured peptides found in venoms of predatory marine gastropods of the genus Conus. They are diverse yet exhibit superior stability, potency, and selectivity for various target receptors and subtypes; hence, they were proven valuable probes for drug discovery studies and models for protein evolution. The data structure of conotoxin peptide sequences in each gene superfamily was analyzed. Feature extraction showed diet- and geographical region-specific gene superfamilies. Using fast-Fourier transform (FFT) and principal component analysis (PCA), data structures indicated patterns of sequence similarity in conopeptides isolated in the same diet type. Clusters based on diet are prominent in the PCA plots and dendrograms. PCA clustering, node grouping, and feature extraction suggest the increasing role of dietary preference, providing insights on the driving force that pushed conotoxins to diverge and diversify.
1 citations
01 Oct 2022
TL;DR: In this article , a computational approach was used to bind 19 α-conotoxins from the A superfamily on a bacterial voltage-gated sodium channel (NavMs) receptor from the Magnetococcus sp. (strain MC-1).
Abstract: The α-conotoxins are neurotoxic peptides produced during predation and defense mechanisms of Conus organisms. Previous studies focused on their binding with nicotinic acetylcholine receptors (nAChRs) only as binding with other neuroreceptors such as voltage-gated sodium channels were not observed. In this study, a computational approach was used to bind 19 α-conotoxins from the A superfamily on a bacterial voltage-gated sodium channel (NavMs) receptor from the Magnetococcus sp. (strain MC-1). Preparation was performed using PyMOL, and the ligand-receptor interactions were simulated using DINC 2.0, an incremental docking approach based on genetic algorithm. Based on the binding energies (in kcal/mol), the reaction between the voltage-gated sodium channel and α-conotoxins is both a favorable spontaneous process thermodynamically and characteristic to the pharmacological class due to highly negative and close range of values. Additionally, RMSD values provided further insights on different channel conformations after molecular docking studies. Lastly, conotoxin BuIA (PDB ID 2I28) with a binding energy of −6.87 $$\pm$$ 0.2357 kcal/mol is the most probable active conotoxin. Findings of this study are significant for α-conotoxins as potential novel drugs for voltage-gated sodium channels which are commonly involved in neurological diseases.
References
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TL;DR: The creation of the wwPDB formalizes the international character of the PDB and ensures that the archive remains single and uniform, and provides a mechanism to ensure consistent data for software developers and users worldwide.
Abstract: mentation will be kept publicly available and the distribution sites will mirror the PDB archive using identical contents and subdirectory structure. However, each member of the wwPDB will be able to develop its own web site, with a unique view of the primary data, providing a variety of tools and resources for the global community. An Advisory Board consisting of appointees from the wwPDB, the International Union of Crystallography and the International Council on Magnetic Resonance in Biological Systems will provide guidance through annual meetings with the wwPDB consortium. This board is responsible for reviewing and determining policy as well as providing a forum for resolving issues related to the wwPDB. Specific details about the Advisory Board can be found in the wwPDB charter, available on the wwPDB web site. The RCSB is the ‘archive keeper’ of wwPDB. It has sole write access to the PDB archive and control over directory structure and contents, as well as responsibility for distributing new PDB identifiers to all deposition sites. The PDB archive is a collection of flat files in the legacy PDB file format 3 and in the mmCIF 4 format that follows the PDB exchange dictionary (http://deposit.pdb.org/ mmcif/). This dictionary describes the syntax and semantics of PDB data that are processed and exchanged during the process of data annotation. It was designed to provide consistency in data produced in structure laboratories, processed by the wwPDB members and used in bioinformatics applications. The PDB archive does not include the websites, browsers, software and database query engines developed by researchers worldwide. The members of the wwPDB will jointly agree to any modifications or extensions to the PDB exchange dictionary. As data technology progresses, other data formats (such as XML) and delivery methods may be included in the official PDB archive if all the wwPDB members concur on the alteration. Any new formats will follow the naming and description conventions of the PDB exchange dictionary. In addition, the legacy PDB format would not be modified unless there is a compelling reason for a change. Should such a situation occur, all three wwPDB members would have to agree on the changes and give the structural biology community 90 days advance notice. The creation of the wwPDB formalizes the international character of the PDB and ensures that the archive remains single and uniform. It provides a mechanism to ensure consistent data for software developers and users worldwide. We hope that this will encourage individual creativity in developing tools for presenting structural data, which could benefit the scientific research community in general.
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1,680 citations
27 Sep 2003
TL;DR: The advantages of the FATCAT approach are illustrated by several examples of comparison between proteins known to adopt different conformations, where the FATcAT algorithm achieves more accurate structure alignments than current methods, while at the same time introducing fewer hinges.
Abstract: Motivation: Protein structures are flexible and undergo structural rearrangements as part of their function, and ye tm ost existing protein structure comparison methods treat them as rigid bodies, which may lead to incorrect alignment. Results: We have developed the Flexible structure AlignmenT by Chaining AFPs (Aligned Fragment Pairs) with Twists (FATCAT), a new method for structural alignment of proteins. The FATCAT approach simultaneously addresses the two major goals of flexible structure alignment; optimizing the alignment and minimizing the number of rigid-body movements (twists) around pivot points (hinges) introduced in the reference protein. In contrast, currently existing flexible structure alignment programs treat the hinge detection as a post-process of a standard rigid body alignment. We illustrate the advantages of the FATCAT approach by several examples of comparison between proteins known to adopt different conformations, where the FATCAT algorithm achieves more accurate structure alignments than current methods, while at the same time introducing fewer hinges.
608 citations
"Alpha-family of Conotoxins: An Anal..." refers background in this paper
...The structure of several conopeptides has been solved either by NMR or X-ray analysis [11], [14], [29]....
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TL;DR: A 16-amino acid peptide from the venom of the marine snail Conus magus was identified by electrophysiologically screening venom fractions against cloned nicotinic receptors expressed in Xenopus oocytes.
461 citations
TL;DR: Several methods routinely used to compare computational models to experimental answers in several modeling assessments are described and the importance of using combined measures, utility-based measures, and the role of the distributions derived from the pairs of experimental structures in interpreting the results are illustrated.
Abstract: Despite its apparent simplicity, the problem of quantifying the differences between two structures of the same protein or complex is nontrivial and continues evolving. In this chapter, we described several methods routinely used to compare computational models to experimental answers in several modeling assessments. The two major classes of measures, positional distance-based and contact-based, are presented, compared, and analyzed. The most popular measure of the first class, the global RMSD, is shown to be the least representative of the degree of structural similarity because it is dominated by the largest error. Several distance-dependent algorithms designed to attenuate the drawbacks of RMSD are described. Measures of the second class, contact-based, are shown to be more robust and relevant. We also illustrate the importance of using combined measures, utility-based measures, and the role of the distributions derived from the pairs of experimental structures in interpreting the results.
376 citations
"Alpha-family of Conotoxins: An Anal..." refers background in this paper
...There is very little sequence similarity between the primary structures of the mature peptides aside from the Cys residues patterns [10], [16]....
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