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However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this study, we present a comparative investigation using electrophysiological approaches and computational analysis between two alpha toxins from evolutionarily close scorpion species of the genus Tityus, namely, Tst3 and Ts3 from T. stigmurus and T. serrulatus, respectively. These toxins exhibit three natural substitutions near the C-terminal region, which is directly involved in the interaction between alpha toxins and Nav channels. Additionally, we characterized the activity of the Tst3 toxin on Nav1.1-Nav1.7 channels. The three natural changes between the toxins did not alter sensitivity to Nav1.4, maintaining similar intensities regarding their ability to alter opening probabilities, delay fast inactivation, and induce persistent currents. Computational analysis demonstrated a preference for the down conformation of VSD4 and a shift in the conformational equilibrium towards this state. This illustrates that the sequence of these toxins retained the necessary information, even with alterations in the interaction site region. Through electrophysiological and computational analyses, screening of the Tst3 toxin on sodium isoform revealed its classification as a classic \u03b1-NaTx with a broad spectrum of activity. It effectively delays fast inactivation across all tested isoforms. Structural analysis of molecular energetics at the interface of the VSD4-Tst3 complex further confirmed this effect.<\/jats:p>","DOI":"10.3390\/toxins16060257","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T05:58:00Z","timestamp":1717394280000},"page":"257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling Tst3, a Multi-Target Gating Modifier Scorpion \u03b1 Toxin from Tityus stigmurus Venom of Northeast Brazil: Evaluation and Comparison with Well-Studied Ts3 Toxin of Tityus serrulatus"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0962-099X","authenticated-orcid":false,"given":"Diogo Vieira","family":"Tibery","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Neurofarmacologia, Departamento de Ci\u00eancias Fisiol\u00f3gicas, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4331-0266","authenticated-orcid":false,"given":"Jo\u00e3o Antonio Alves","family":"Nunes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Te\u00f3rica e Computacional (LBTC), Departamento de Biologia Celular, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Oliveira","family":"da Mata","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurofarmacologia, Departamento de Ci\u00eancias Fisiol\u00f3gicas, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2264-5016","authenticated-orcid":false,"given":"Luis Felipe Santos","family":"Menezes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurofarmacologia, Departamento de Ci\u00eancias Fisiol\u00f3gicas, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo Carlos Barros","family":"de Souza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurofarmacologia, Departamento de Ci\u00eancias Fisiol\u00f3gicas, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4221-9580","authenticated-orcid":false,"given":"Matheus de Freitas","family":"Fernandes-Pedrosa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecnologia e Biotecnologia Farmac\u00eautica, Departamento de Farm\u00e1cia, Universidade Federal do Rio Grande do Norte (UFRN), Natal 59012-570, Rio Grande do Norte, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-3205","authenticated-orcid":false,"given":"Werner","family":"Treptow","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Te\u00f3rica e Computacional (LBTC), Departamento de Biologia Celular, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8239-4055","authenticated-orcid":false,"given":"Elisabeth Ferroni","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Neurofarmacologia, Departamento de Ci\u00eancias Fisiol\u00f3gicas, Universidade de Bras\u00edlia (UnB), Bras\u00edlia 70910-900, Distrito Federal, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1085\/jgp.201511492","article-title":"The Hitchhiker\u2019s Guide to the Voltage-Gated Sodium Channel Galaxy","volume":"147","author":"Ahern","year":"2016","journal-title":"J. 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