{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T11:56:40Z","timestamp":1793707000829,"version":"4.6.1"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    Venom peptides are potent and selective modulators of voltage-gated ion channels that regulate neuronal function both in health and in disease. We previously identified the spider venom peptide Tap1a from the Venezuelan tarantula\n                    <jats:italic>Theraphosa apophysis<\/jats:italic>\n                    that targeted multiple voltage-gated sodium and calcium channels in visceral pain pathways and inhibited visceral mechano-sensing neurons contributing to irritable bowel syndrome. 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 features characteristic of spider peptides belonging to family NaSpTx1. In order to speed up the development of optimized Na\n                    <jats:sub>V<\/jats:sub>\n                    -targeting peptides with greater inhibitory potency and enhanced\n                    <jats:italic>in vivo<\/jats:italic>\n                    activity, we tested the hypothesis that incorporating residues identified from other optimized NaSpTx1 peptides into Tap1a could also optimize its potency for Na\n                    <jats:sub>V<\/jats:sub>\n                    s. Applying this approach, we designed the peptides Tap1a-OPT1 and Tap1a-OPT2 exhibiting significant increased potency for Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.3, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.6 and Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 involved in several neurological disorders including acute and chronic pain, motor neuron disease and epilepsy. Tap1a-OPT1 showed increased potency for the off-target Na\n                    <jats:sub>V<\/jats:sub>\n                    1.4, while this off-target activity was absent in Tap1a-OPT2. This enhanced potency arose through a slowed off-rate mechanism. Optimized inhibition of Na\n                    <jats:sub>V<\/jats:sub>\n                    channels observed\n                    <jats:italic>in vitro<\/jats:italic>\n                    translated\n                    <jats:italic>in vivo<\/jats:italic>\n                    , with reversal of nocifensive behaviours in a murine model of Na\n                    <jats:sub>V<\/jats:sub>\n                    -mediated pain also enhanced by Tap1a-OPT. Molecular docking studies suggested that improved interactions within loops 3 and 4, and C-terminal of Tap1a-OPT and the Na\n                    <jats:sub>V<\/jats:sub>\n                    channel voltage-sensor domain II were the main drivers of potency optimization. Overall, the rationally designed peptide Tap1a-OPT displayed new and refined structure-function features which are likely the major contributors to its enhanced bioactive properties observed\n                    <jats:italic>in vivo<\/jats:italic>\n                    . This work contributes to the rapid engineering and optimization of potent spider peptides multi-targeting Na\n                    <jats:sub>V<\/jats:sub>\n                    channels, and the research into novel drugs to treat neurological diseases.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2021.742457","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T02:35:25Z","timestamp":1632191725000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Engineering of a Spider Peptide via Conserved Structure-Function Traits Optimizes Sodium Channel Inhibition In Vitro and Anti-Nociception In Vivo"],"prefix":"10.3389","volume":"8","author":[{"given":"H.","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. E.","family":"Mawlawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. R.","family":"Deuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Jami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. C.","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.bbamem.2017.01.020","article-title":"Spider Peptide Toxin HwTx-IV Engineered to Bind to Lipid Membranes Has an Increased Inhibitory Potency at Human Voltage-Gated Sodium Channel hNa V 1.7","volume":"1859","author":"Agwa","year":"2017","journal-title":"Biochim. Biophys. Acta (Bba) - Biomembranes"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5067","DOI":"10.1074\/jbc.ra119.012281","article-title":"Manipulation of a Spider Peptide Toxin Alters its Affinity for Lipid Bilayers and Potency and Selectivity for Voltage-Gated Sodium Channel Subtype 1.7","volume":"295","author":"Agwa","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL Workspace: a Web-Based Environment for Protein Structure Homology Modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1756-6606-7-36","article-title":"Block of T-type Calcium Channels by Protoxins I and II","volume":"7","author":"Bladen","year":"2014","journal-title":"Mol. Brain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.3389\/fphar.2020.01132","article-title":"From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery","volume":"11","author":"Bordon","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nature07473","article-title":"Deconstructing Voltage Sensor Function and Pharmacology in Sodium Channels","volume":"456","author":"Bosmans","year":"2008","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.peptides.2014.09.005","article-title":"Mapping the Interaction Site for the Tarantula Toxin Hainantoxin-IV (\u03b2-TRTX-Hn2a) in the Voltage Sensor Module of Domain II of Voltage-Gated Sodium Channels","volume":"68","author":"Cai","year":"2015","journal-title":"Peptides"},{"key":"B8","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1097\/j.pain.0000000000002041","article-title":"A Spider-Venom Peptide with Multitarget Activity on Sodium and Calcium Channels Alleviates Chronic Visceral Pain in a Model of Irritable Bowel Syndrome","volume":"162","author":"Cardoso","year":"2021","journal-title":"Pain"},{"key":"B9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1124\/mol.115.098178","article-title":"Identification and Characterization of ProTx-III [\u03bc-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma Pruriens","volume":"88","author":"Cardoso","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1111\/bph.13865","article-title":"Modulatory Features of the Novel Spider Toxin \u03bc\u2010TRTX\u2010Df1a Isolated from the Venom of the Spider Davus Fasciatus","volume":"174","author":"Cardoso","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1097\/spc.0000000000000335","article-title":"Toxins in Pain","volume":"12","author":"Cardoso","year":"2018","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2138","DOI":"10.1111\/bph.13962","article-title":"Sodium Channels and Pain: from Toxins to Therapies","volume":"175","author":"Cardoso","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"366","DOI":"10.3389\/fphar.2019.00366","article-title":"Structure-Function and Therapeutic Potential of Spider Venom-Derived Cysteine Knot Peptides Targeting Sodium Channels","volume":"10","author":"Cardoso","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"114107","DOI":"10.1016\/j.bcp.2020.114107","article-title":"Multi-targeting Sodium and Calcium Channels Using Venom Peptides for the Treatment of Complex Ion Channels-Related Diseases","volume":"181","author":"Cardoso","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1007\/s11064-017-2314-9","article-title":"Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy","volume":"42","author":"Catterall","year":"2017","journal-title":"Neurochem. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1001\/jama.2015.0954","article-title":"Irritable Bowel Syndrome","volume":"313","author":"Chey","year":"2015","journal-title":"JAMA"},{"key":"B17","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1093\/pm\/pny132","article-title":"Intrathecal Therapy for Chronic Pain: a Review of Morphine and Ziconotide as Firstline Options","volume":"20","author":"Deer","year":"2019","journal-title":"Pain Med."},{"key":"B18","volume-title":"The PyMOL Molecular Graphics System","author":"DeLano","year":"2002"},{"key":"B19","doi-asserted-by":"publisher","first-page":"40883","DOI":"10.1038\/srep40883","article-title":"Pharmacological Characterisation of the Highly NaV1.7 Selective Spider Venom Peptide Pn3a","volume":"7","author":"Deuis","year":"2017","journal-title":"Sci. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3390\/toxins8030078","article-title":"Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain","volume":"8","author":"Deuis","year":"2016","journal-title":"Toxins"},{"key":"B21","doi-asserted-by":"publisher","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: an Automated Pipeline for the Setup of Poisson-Boltzmann Electrostatics Calculations","volume":"32","author":"Dolinsky","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"16014","DOI":"10.1038\/nrdp.2016.14","article-title":"Irritable Bowel Syndrome","volume":"2","author":"Enck","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B23","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1113\/jp273461","article-title":"Voltage-gated Sodium Channels: (NaV)igating the Field to Determine Their Contribution to Visceral Nociception","volume":"596","author":"Erickson","year":"2018","journal-title":"J. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2618","DOI":"10.1152\/jn.00717.2014","article-title":"Experimental and Computational Evidence for an Essential Role of NaV1.6 in Spike Initiation at Stretch-Sensitive Colorectal Afferent Endings","volume":"113","author":"Feng","year":"2015","journal-title":"J. Neurophysiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1021\/bi00815a005","article-title":"Isolation of Bradykinin-Potentiating Peptides from Bothrops jararaca Venom","volume":"9","author":"Ferreira","year":"1970","journal-title":"Biochemistry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"39662","DOI":"10.1038\/srep39662","article-title":"Insensitivity to Pain Induced by a Potent Selective Closed-State Nav1.7 Inhibitor","volume":"7","author":"Flinspach","year":"2017","journal-title":"Sci. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.1097\/j.pain.0000000000001368","article-title":"Tetrodotoxin-sensitive Voltage-Gated Sodium Channels Regulate Bladder Afferent Responses to Distension","volume":"159","author":"Grundy","year":"2018","journal-title":"Pain"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0243645","DOI":"10.1371\/journal.pone.0243645","article-title":"Transfection Methods for High-Throughput Cellular Assays of Voltage-Gated Calcium and Sodium Channels Involved in Pain","volume":"16","author":"Hasan","year":"2020","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"17049","DOI":"10.1074\/jbc.m116.729095","article-title":"Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for its Inhibition of Human Voltage-Gated Sodium Channel NaV1.7","volume":"291","author":"Henriques","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.toxicon.2012.04.337","article-title":"Spider-venom Peptides that Target Voltage-Gated Sodium Channels: Pharmacological Tools and Potential Therapeutic Leads","volume":"60","author":"Klint","year":"2012","journal-title":"Toxicon"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1111\/bph.13081","article-title":"Seven Novel Modulators of the Analgesic Target NaV1.7 Uncovered Using a High-Throughput Venom-Based Discovery Approach","volume":"172","author":"Klint","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1007\/s10867-016-9411-x","article-title":"Mutant SOD1 Protein Increases Nav1.3 Channel Excitability","volume":"42","author":"Kubat \u00d6ktem","year":"2016","journal-title":"J. Biol. Phys."},{"key":"B33","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1021\/acschembio.8b00989","article-title":"Peptide-membrane Interactions Affect the Inhibitory Potency and Selectivity of Spider Toxins ProTx-II and GpTx-1","volume":"14","author":"Lawrence","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.2174\/09298665113206660119","article-title":"Analgesic Effects of Huwentoxin-IV on Animal Models of Inflammatory and Neuropathic Pain","volume":"21","author":"Liu","year":"2014","journal-title":"Protein Pept. Lett."},{"key":"B35","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1124\/mol.106.022970","article-title":"Potent Modulation of the Voltage-Gated Sodium Channel Nav1.7 by OD1, a Toxin from the Scorpion Odonthobuthus Doriae","volume":"70","author":"Maertens","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"14734","DOI":"10.1021\/bi026546a","article-title":"Two Tarantula Peptides Inhibit Activation of Multiple Sodium Channels\u2020","volume":"41","author":"Middleton","year":"2002","journal-title":"Biochemistry"},{"key":"B37","doi-asserted-by":"publisher","first-page":"22707","DOI":"10.1074\/jbc.m113.461392","article-title":"Analysis of the Structural and Molecular Basis of Voltage-Sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (\u03bc-TRTX-Hh2a)","volume":"288","author":"Minassian","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1021\/acsptsci.0c00002","article-title":"Mapping the Molecular Surface of the Analgesic NaV1.7-Selective Peptide Pn3a Reveals Residues Essential for Membrane and Channel Interactions","volume":"3","author":"Mueller","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1021\/jm501765v","article-title":"Engineering Potent and Selective Analogues of GpTx-1, a Tarantula Venom Peptide Antagonist of the NaV1.7 Sodium Channel","volume":"58","author":"Murray","year":"2015","journal-title":"J. Med. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2704","DOI":"10.1021\/acs.jmedchem.5b01947","article-title":"Single Residue Substitutions that Confer Voltage-Gated Sodium Ion Channel Subtype Selectivity in the NaV1.7 Inhibitory Peptide GpTx-1","volume":"59","author":"Murray","year":"2016","journal-title":"J. Med. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nature17976","article-title":"Selective Spider Toxins Reveal a Role for the Nav1.1 Channel in Mechanical Pain","volume":"534","author":"Osteen","year":"2016","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"eaau2486","DOI":"10.1126\/science.aau2486","article-title":"Structure of the Human Voltage-Gated Sodium Channel Nav1.4 in Complex with \u03b21","volume":"362","author":"Pan","year":"2018","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1126\/science.aaw2999","article-title":"Molecular Basis for Pore Blockade of Human Na+ Channel Nav1.2 by the \u03bc-conotoxin KIIIA","volume":"363","author":"Pan","year":"2019","journal-title":"Science"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e2100066118","DOI":"10.1073\/pnas.2100066118","article-title":"Comparative Structural Analysis of Human NaV1.1 and NaV1.5 Reveals Mutational Hotspots for Sodium Channelopathies","volume":"118","author":"Pan","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B45","doi-asserted-by":"publisher","first-page":"E641","DOI":"10.1093\/neuros\/nyz125","article-title":"Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults with Newly Diagnosed or Recurrent Gliomas","volume":"85","author":"Patil","year":"2019","journal-title":"Neurosurgery"},{"key":"B46","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1096\/fj.03-1398bkt","article-title":"From viper's Venom to Drug Design: Treating Hypertension","volume":"18","author":"Patlak","year":"2004","journal-title":"FASEB j."},{"key":"B47","doi-asserted-by":"publisher","first-page":"529","DOI":"10.3390\/md13010529","article-title":"Development of Highly Selective Kv1.3-Blocking Peptides Based on the Sea Anemone Peptide ShK","volume":"13","author":"Pennington","year":"2015","journal-title":"Mar. Drugs"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2738","DOI":"10.1016\/j.bmc.2017.09.029","article-title":"Peptide Therapeutics from Venom: Current Status and Potential","volume":"26","author":"Pennington","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"12773","DOI":"10.1021\/acs.jmedchem.0c01107","article-title":"Two for the price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency","volume":"63","author":"Peschel","year":"2020","journal-title":"J. Med. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.toxicon.2006.09.014","article-title":"ProTx-I and ProTx-II: Gating Modifiers of Voltage-Gated Sodium Channels","volume":"49","author":"Priest","year":"2007","journal-title":"Toxicon"},{"key":"B51","doi-asserted-by":"publisher","first-page":"e0173551","DOI":"10.1371\/journal.pone.0173551","article-title":"The Structure, Dynamics and Selectivity Profile of a NaV1.7 Potency-Optimised Huwentoxin-IV Variant","volume":"12","author":"Rahnama","year":"2017","journal-title":"PLoS One"},{"key":"B52","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.peptides.2013.03.011","article-title":"Potency Optimization of Huwentoxin-IV on hNav1.7: a Neurotoxin TTX-S Sodium-Channel Antagonist from the Venom of the Chinese Bird-Eating Spider Selenocosmia Huwena","volume":"44","author":"Revell","year":"2013","journal-title":"Peptides"},{"key":"B53","doi-asserted-by":"publisher","first-page":"E8077","DOI":"10.1073\/pnas.1804764115","article-title":"Selective NaV1.1 Activation Rescues Dravet Syndrome Mice from Seizures and Premature Death","volume":"115","author":"Richards","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B54","doi-asserted-by":"publisher","first-page":"e65984","DOI":"10.1371\/journal.pone.0065984","article-title":"Native Pyroglutamation of Huwentoxin-IV: a post-translational Modification that Increases the Trapping Ability to the Sodium Channel","volume":"8","author":"Rong","year":"2013","journal-title":"PLoS One"},{"key":"B55","doi-asserted-by":"publisher","first-page":"104532","DOI":"10.1016\/j.nbd.2019.104532","article-title":"Modified Age-dependent Expression of NaV1.6 in an ALS Model Correlates with Motor Cortex Excitability Alterations","volume":"130","author":"Saba","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"B56","doi-asserted-by":"publisher","first-page":"e121000","DOI":"10.1172\/jci.insight.121000","article-title":"NaV1.1 Inhibition Can Reduce Visceral Hypersensitivity","volume":"3","author":"Salvatierra","year":"2018","journal-title":"JCI Insight"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1124\/mol.108.047670","article-title":"ProTx-II, a Selective Inhibitor of NaV1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors","volume":"74","author":"Schmalhofer","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"13974","DOI":"10.1074\/jbc.m116.725978","article-title":"Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain","volume":"291","author":"Shcherbatko","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1126\/science.aaw2493","article-title":"Structures of Human Nav1.7 Channel in Complex with Auxiliary Subunits and Animal Toxins","volume":"363","author":"Shen","year":"2019","journal-title":"Science"},{"key":"B60","doi-asserted-by":"publisher","first-page":"11","DOI":"10.2147\/JEP.S79973","article-title":"Antihyperalgesic Effects of ProTx-II, a Nav1.7 Antagonist, and A803467, a Nav1.8 Antagonist, in Diabetic Mice","volume":"7","author":"Tanaka","year":"2015","journal-title":"J. Exp. Pharmacol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.jmb.2015.09.014","article-title":"The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes","volume":"428","author":"van Zundert","year":"2016","journal-title":"J. Mol. Biol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.molcel.2020.10.039","article-title":"Structural Basis for High-Affinity Trapping of the NaV1.7 Channel in its Resting State by Tarantula Toxin","volume":"81","author":"Wisedchaisri","year":"2021","journal-title":"Mol. Cell"},{"key":"B63","doi-asserted-by":"publisher","first-page":"27300","DOI":"10.1074\/jbc.m708447200","article-title":"Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain Ii Voltage Sensor in the Closed Configuration","volume":"283","author":"Xiao","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1124\/mol.110.066332","article-title":"The Tarantula Toxins ProTx-II and Huwentoxin-IV Differentially Interact with Human Nav1.7 Voltage Sensors to Inhibit Channel Activation and Inactivation","volume":"78","author":"Xiao","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"27301","DOI":"10.1074\/jbc.m111.246876","article-title":"Common Molecular Determinants of Tarantula Huwentoxin-IV Inhibition of Na+ Channel Voltage Sensors in Domains II and IV","volume":"286","author":"Xiao","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B66","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.cell.2018.12.018","article-title":"Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin","volume":"176","author":"Xu","year":"2019","journal-title":"Cell"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.742457\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T02:35:31Z","timestamp":1632191731000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.742457\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,21]]},"references-count":66,"alternative-id":["10.3389\/fmolb.2021.742457"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2021.742457","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,21]]},"article-number":"742457"}}