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Determination of the μ-Conotoxin PIIIA Specificity Against Voltage-Gated Sodium Channels from Binding Energy Calculations

Fangling Chen, Wenxin Huang, Tao Jiang, Rilei Yu
2018 Marine Drugs  
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

Anatoly Shcherbatko, Andrea Rossi, Davide Foletti, Guoyun Zhu, Oren Bogin, Meritxell Galindo Casas, Mathias Rickert, Adela Hasa-Moreno, Victor Bartsevich, Andreas Crameri, Alexander R. Steiner, Robert Henningsen (+5 others)
2016 Journal of Biological Chemistry  
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  
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

Marc Rogers, Nace Zidar, Danijel Kikelj, Robert W. Kirby
2016 Assay and drug development technologies  
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

Nicolas, Zoukimian, Bosmans, Montnach, Diochot, Cuypers, De Waard, Béroud, Mebs, Craik, Boturyn, Lazdunski (+2 others)
2019 Toxins  
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

Daria Slowik, Richard Henderson
2015 Biochimica et Biophysica Acta - Biomembranes  
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

David H. Hackos, Shivani Ahuja, Susmith Mukund, Lunbin Deng, Kuldip Khakh, Elaine Chang, Clint Young, Sophia Lin, J.P. Johnson, Daniel F. Ortwine, Brian S. Safina, Daniel P. Sutherlin (+3 others)
2016 Biophysical Journal  
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

S. Ahuja, S. Mukund, L. Deng, K. Khakh, E. Chang, H. Ho, S. Shriver, C. Young, S. Lin, J. P. Johnson, P. Wu, J. Li (+23 others)
2015 Science  
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

Tomas Koltai
2015 F1000Research  
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

Shunyi Zhu, Steve Peigneur, Bin Gao, Xiuxiu Lu, Chunyang Cao, Jan Tytgat
2011 Molecular & Cellular Proteomics  
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

H. Hu, S. E. Mawlawi, T. Zhao, J. R. Deuis, S. Jami, I. Vetter, R. J. Lewis, F. C. Cardoso
2021 Frontiers in Molecular Biosciences  
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]

Eedann McCord, Goragot Wisedchaisri, William A Catterall
2020 biorxiv/medrxiv   pre-print
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

Desirée Kaufmann, Alesia Tietze, Daniel Tietze
2019 Marine Drugs  
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

O Knapp, ST Nevin, T Yasuda, N Lawrence, RJ Lewis, DJ Adams
2012 British Journal of Pharmacology  
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

Yuying Wang, Joel M. Brittain, Brian W. Jarecki, Ki Duk Park, Sarah M. Wilson, Bo Wang, Rachel Hale, Samy O. Meroueh, Theodore R. Cummins, Rajesh Khanna
2010 Journal of Biological Chemistry  
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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