{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:54:29Z","timestamp":1787590469106,"version":"build-2736575974"},"reference-count":63,"publisher":"Portland Press Ltd.","issue":"14","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,7,30]]},"abstract":"<jats:p>The interaction of insect-selective scorpion depressant \u03b2-toxins (LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus) with the Blattella germanica sodium channel, BgNav1-1a, was investigated using site-directed mutagenesis, electrophysiological analyses, and structural modeling. Focusing on the pharmacologically defined binding site-4 of scorpion \u03b2-toxins at the voltage-sensing domain II (VSD-II), we found that charge neutralization of D802 in VSD-II greatly enhanced the channel sensitivity to Lqh-dprIT3. This was consistent with the high sensitivity of the splice variant BgNav2-1, bearing G802, to Lqh-dprIT3, and low sensitivity of BgNav2-1 mutant, G802D, to the toxin. Further mutational and electrophysiological analyses revealed that the sensitivity of the WT\u2009=\u2009D802E\u2009&amp;lt;\u2009D802G\u2009&amp;lt;\u2009D802A\u2009&amp;lt;\u2009D802K channel mutants to Lqh-dprIT3 correlated with the depolarizing shifts of activation in toxin-free channels. However, the sensitivity of single mutants involving IIS4 basic residues (K4E\u2009=\u2009WT\u2009&amp;lt;&amp;lt;\u2009R1E\u2009&amp;lt;\u2009R2E\u2009&amp;lt;\u2009R3E) or double mutants (D802K\u2009=\u2009K4E\/D802K\u2009=\u2009R3E\/D802K\u2009&amp;gt;\u2009R2E\/D802K\u2009&amp;gt;\u2009R1E\/D802K\u2009&amp;gt;\u2009WT) did not correlate with the activation shifts. Using the cryo-EM structure of the Periplaneta americana channel, NavPaS, as a template and the crystal structure of LqhIT2, we constructed structural models of LqhIT2 and Lqh-dprIT3-c in complex with BgNav1-1a. These models along with the mutational analysis suggest that depressant toxins approach the salt-bridge between R1 and D802 at VSD-II to form contacts with linkers IIS1\u2013S2, IIS3\u2013S4, IIIP5\u2013P1 and IIIP2\u2013S6. Elimination of this salt-bridge enables deeper penetration of the toxin into a VSD-II gorge to form new contacts with the channel, leading to increased channel sensitivity to Lqh-dprIT3.<\/jats:p>","DOI":"10.1042\/bcj20210336","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T04:07:10Z","timestamp":1625112430000},"page":"2843-2869","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Mapping the interaction surface of scorpion \u03b2-toxins with an insect sodium channel"],"prefix":"10.1042","volume":"478","author":[{"given":"Boris S.","family":"Zhorov","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton L8S 4K1 Canada"},{"name":"Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia"},{"name":"Almazov National Medical Research Centre, St. Petersburg 197341, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhe","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Entomology, Michigan State University, East Lansing, MI 48824, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Entomology, Michigan State University, East Lansing, MI 48824, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningguang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Entomology, Michigan State University, East Lansing, MI 48824, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Plant Molecular Biology & Ecology, George S. 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