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Determination of the μ-Conotoxin PIIIA Specificity Against Voltage-Gated Sodium Channels from Binding Energy Calculations
2018
Marine Drugs
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In this study, a model of Na V 1.4 bound with µ-conotoxin PIIIA complex was constructed using homology modeling, docking, molecular dynamic simulations and binding energy calculations. ...
The binding affinities calculated using MMGB/SA and umbrella sampling are correlated with the experimental values, with the former and the latter giving correlation coefficient of 0.41 (R 2 ) and 0.68 ...
The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. ...
doi:10.3390/md16050153
pmid:29735899
pmcid:PMC5983284
fatcat:vigmlnfmbnfyvfmczcizrgxvqm
Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain
2016
Journal of Biological Chemistry
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The prominent role of voltage-gated sodium channel 1.7 (Nav1.7) in nociception was revealed by remarkable human clinical and genetic evidence. ...
The resulting microproteins are highly potent (IC 50 to Nav1.7 of 2.5 nM) and selective. ...
Acknowledgements: The authors thank Santiago Farias for MS analysis.
Conflict of interest: All authors were employees of Pfizer, Amunix, and Sutro Biopharma at the time of the study. ...
doi:10.1074/jbc.m116.725978
pmid:27129258
pmcid:PMC4933158
fatcat:jase3hmoqzhylkv752x4xrbvdq
Voltage-gated Na Channels
2008
Biophysical Journal
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Molecular modeling of the protein sequence and point mutations have shown that Na channel selectivity results from a narrow ring at the bottom of an outer vestibule composed of the side chains of aspartate ...
Overall, our results suggest that the simpler, tetrameric NaChBac channel is even more selective for Na than are eukaryotic Na V channels, and that NaChBac achieves this high selectivity by a unique molecular ...
Our models suggest a key role of Phe36 and Tyr41 in the binding of both toxins to the channel, while Tyr35, Trp37 and Trp40 can account for the higher affinity of PnTx2-6. ...
doi:10.1016/s0006-3495(08)79187-2
fatcat:spzrujwdfjftlkopel6byuppjq
Characterization of Endogenous Sodium Channels in the ND7-23 Neuroblastoma Cell Line: Implications for Use as a Heterologous Ion Channel Expression System Suitable for Automated Patch Clamp Screening
2016
Assay and drug development technologies
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determined which subtypes contribute to functional channels at the cell surface. ...
The potency and subtype selectivity of the ligands (Icagen compound 68 from patent US-20060025415-A1-20060202, 4,9 anhydro TTX, and Protoxin-II) were established in human Nav1.3, Nav1.6, and Nav1.7 channel ...
Nav1.x and ND7-23 automated patch clamp assays at Xention. ...
doi:10.1089/adt.2016.704
pmid:26991361
pmcid:PMC4800267
fatcat:qqj4rtykpvcylefbhsyrtqilte
Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1
2019
Toxins
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We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. ...
PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain. ...
Goldin, Univ. of California, Irvine, USA for sharing rNa v 1.1, rNa v 1. ...
doi:10.3390/toxins11060367
pmid:31234412
pmcid:PMC6628435
fatcat:szpozoqlavhhtlc5sy2fcnpzkm
Benchmarking the stability of human detergent-solubilised voltage-gated sodium channels for structural studies using eel as a reference
2015
Biochimica et Biophysica Acta - Biomembranes
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With the ultimate goal of detailed structural analysis of mammalian and particularly human voltage-gated sodium channels (VGSCs), we have investigated the relative stability of human and rat VGSCs and ...
methods that require greater stability such as crystallisation and X-ray crystallography, will require further stabilisation of the channel. ...
Finally we thank Bonnie Wallace (Birkbeck College, London) for providing initial samples of frozen eel electroplax, and for valuable discussions. ...
doi:10.1016/j.bbamem.2015.03.021
pmid:25838126
pmcid:PMC4557063
fatcat:v7jnhkohivfn5hgutsvvf6q7aq
Structural Basis of Nav1.7 Inhibition by an Isoform-Selective Small Molecule Antagonist
2016
Biophysical Journal
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pain that selectively target Nav1.7. ▪ ...
ACKNOWLEDGMENTS We thank our colleagues in the Structural Biology, Biology, Neuroscience, Discovery Chemistry, Biochemical and Cellular Pharmacology, and Chemistry Departments at Genentech and Xenon for ...
Use of the Stanford Synchrotron Radiation Lightsource SSRL 12-12 at Stanford Linear Accelerator Center National Accelerator Laboratory is supported by the U.S. ...
doi:10.1016/j.bpj.2015.11.249
fatcat:dhx2sgsgpjdn3d2a6cuxankoum
Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist
2015
Science
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pain that selectively target Nav1.7. ▪ ...
ACKNOWLEDGMENTS We thank our colleagues in the Structural Biology, Biology, Neuroscience, Discovery Chemistry, Biochemical and Cellular Pharmacology, and Chemistry Departments at Genentech and Xenon for ...
Use of the Stanford Synchrotron Radiation Lightsource SSRL 12-12 at Stanford Linear Accelerator Center National Accelerator Laboratory is supported by the U.S. ...
doi:10.1126/science.aac5464
pmid:26680203
fatcat:j5fud56e2vannp54q3nqpubopa
Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs
2015
F1000Research
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Each of them are independently described and analyzed. ...
To determine the exact role of sodium channel proteins in Objective: migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage ...
PHEN blocks Na + channels and has a high affinity for VGSCs in the inactivated state of the channel 61 .Compared with verapamil, lidocaine and carbamacepine, PHEN had an intermediate potency between verapamil ...
doi:10.12688/f1000research.6789.1
pmid:27408684
pmcid:PMC4920216
fatcat:b33bl57ihbgebga5ougrwzpuaa
Evolutionary Diversification ofMesobuthusα-Scorpion Toxins Affecting Sodium Channels
2011
Molecular & Cellular Proteomics
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1 The abbreviations used are: VGSC, voltage-gated sodium channel; 3Ј-UTR, 3Ј-untranslational region; CS␣, cysteine-stabilized ␣-helical and -sheet; MALDI-TOF MS, matrix-assisted laser desorption ionization ...
Evolutionary Diversification of Scorpion Na ؉ Channel Toxins ...
S1 and S2 and Tables S1 to S4 and Appendix. ** These authors contributed equally to this work. The authors have declared no conflicts of interest. ...
doi:10.1074/mcp.m111.012054
pmid:21969612
pmcid:PMC3270107
fatcat:sbddy47x7vcltj6aduz2mqye7q
Engineering of a Spider Peptide via Conserved Structure-Function Traits Optimizes Sodium Channel Inhibition In Vitro and Anti-Nociception In Vivo
2021
Frontiers in Molecular Biosciences
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In this work, alanine scanning and domain activity analysis revealed Tap1a inhibited sodium channels by binding with nanomolar affinity to the voltage-sensor domain II utilising conserved structure-function ...
Optimized inhibition of NaV channels observed in vitro translated in vivo, with reversal of nocifensive behaviours in a murine model of NaV-mediated pain also enhanced by Tap1a-OPT. ...
JD, RL, and IV were supported by research fellowships from the Australian National Health and Medical Research Council (APP1162503, APP1119056, and APP1139961, respectively). ...
doi:10.3389/fmolb.2021.742457
pmid:34621788
pmcid:PMC8490825
fatcat:sepa3juzxbhbvjwvwa3b5jj3te
Broadband Tuning the Voltage Dependence of a Sodium Channel
[article]
2020
biorxiv/medrxiv
pre-print
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Our results demonstrate broadband shifting of VA and VQ of a sodium channel across a range of 240 mV and provide a toolbox of methods and constructs to analyze sodium channel structure and function in ...
acid residues from the extracellular half of the voltage sensor of human NaV1.7 channels. ...
Many experimental results support the sliding helix/helical screw model of voltage sensation. ...
doi:10.1101/2020.11.21.392571
fatcat:3ukbumabjfg5fe4j3svh2kzfju
In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA
2019
Marine Drugs
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Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, and GIIIA, at the voltage-gated potassium channels ...
of the KV1 family, and they were correlated with their experimental activities recently reported by Leipold et al. ...
Results and Discussion According to the experimental results obtained by Leipold et al., a detailed in-silico analysis of the binding mode and the dynamics of µ-PIIIA, µ-SIIIA, and µ-GIIIA on the K V 1 ...
doi:10.3390/md17030180
fatcat:ibjlqgvmlfcvxpxlgf4orpvdgi
Biophysical properties of Nav1.8/Nav1.2 chimeras and inhibition by µO-conotoxin MrVIB
2012
British Journal of Pharmacology
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CONCLUSIONS AND IMPLICATIONS Taken together, these results suggest that domain II of Nav1.8 is an important determinant of MrVIB affinity, highlighting a region of the a-subunit that may allow further ...
To determine which domain confers Nav1.8 a-subunit its biophysical properties and MrVIB binding, we constructed various chimeric channels incorporating sequence from Nav1.8 and the TTX-S Nav1.2 using a ...
II was the major determinant of its high-affinity binding. ...
doi:10.1111/j.1476-5381.2012.01955.x
pmid:22452751
pmcid:PMC3402778
fatcat:nf67swbk4bacvjxitcw7g2kz5u
In SilicoDocking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation
2010
Journal of Biological Chemistry
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channels but the observation that LCM binds to collapsin response mediator protein 2 (CRMP-2) suggests additional mechanisms of action for LCM. ...
Collectively, these results identify key CRMP-2 residues that can coordinate LCM binding thus making it more effective on its primary clinical target. ...
Molecular modeling revealed five pockets capable of binding LCM. ...
doi:10.1074/jbc.m110.128801
pmid:20538611
pmcid:PMC2919092
fatcat:yf4bj5payzhojnqodmgo5yxez4
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