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Cm28 has &amp;lt;40% similarity with other known \u03b1-KTx from scorpions and lacks the typical functional dyad (lysine\u2013tyrosine) required to block KV channels. However, its unique sequence contains the three disulfide-bond traits of the \u03b1-KTx scorpion toxin family. We propose that Cm28 is the first example of a new subfamily of \u03b1-KTxs, registered with the systematic number \u03b1-KTx32.1. Cm28 inhibited voltage-gated K+ channels KV1.2 and KV1.3 with Kd values of 0.96 and 1.3 nM, respectively. There was no significant shift in the conductance\u2013voltage (G-V) relationship for any of the channels in the presence of toxin. Toxin binding kinetics showed that the association and dissociation rates are consistent with a bimolecular interaction between the peptide and the channel. Based on these, we conclude that Cm28 is not a gating modifier but rather a pore blocker. In a selectivity assay, Cm28 at 150 nM concentration (&amp;gt;100\u00d7 Kd value for KV1.3) did not inhibit KV1.5, KV11.1, KCa1.1, and KCa3.1 K+ channels; NaV1.5 and NaV1.4 Na+ channels; or the hHV1 H+ channel but blocked \u223c27% of the KV1.1 current. In a biological functional assay, Cm28 strongly inhibited the expression of the activation markers interleukin-2 receptor and CD40 ligand in anti-CD3\u2013activated human CD4+ effector memory T lymphocytes. Cm28, due to its unique structure, may serve as a template for the generation of novel peptides targeting KV1.3 in autoimmune diseases.<\/jats:p>","DOI":"10.1085\/jgp.202213146","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T13:19:26Z","timestamp":1655212766000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Cm28, a scorpion toxin having a unique primary structure, inhibits KV1.2 and KV1.3 with high affinity"],"prefix":"10.1085","volume":"154","author":[{"given":"Muhammad Umair","family":"Naseem","sequence":"first","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edson","family":"Carcamo-Noriega","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Mexico 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-6931","authenticated-orcid":true,"given":"Jos\u00e9","family":"Beltr\u00e1n-Vidal","sequence":"additional","affiliation":[{"name":"Grupo de Investigaciones Herpetol\u00f3gicas y Toxinol\u00f3gicas, Centro de Investigaciones Biom\u00e9dicas, Departamento de Biolog\u00eda, Facultad de Ciencias Naturales, Exactas y de la Educaci\u00f3n, Universidad del Cauca, Popay\u00e1n, Colombia 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Borrego","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tibor G.","family":"Szanto","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando Z.","family":"Zamudio","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Mexico 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7977-9269","authenticated-orcid":true,"given":"Gustavo","family":"Delgado-Prudencio","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Mexico 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourival D.","family":"Possani","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Mexico 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6227-3301","authenticated-orcid":true,"given":"Gyorgy","family":"Panyi","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,6,14]]},"reference":[{"key":"2023072707434705400_bib1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.febslet.2005.12.073","article-title":"A novel toxin from the venom of the scorpion Tityus trivittatus, is the first member of a new \u03b1-KTX subfamily","volume":"580","author":"Abdel-Mottaleb","year":"2006","journal-title":"FEBS Lett."},{"key":"2023072707434705400_bib2","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1016\/0896-6273(95)90104-3","article-title":"Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins","volume":"15","author":"Aiyar","year":"1995","journal-title":"Neuron"},{"key":"2023072707434705400_bib3","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1007\/s00424-016-1851-4","article-title":"7DHC-induced changes of Kv1. 3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome","volume":"468","author":"Balajthy","year":"2016","journal-title":"Pflugers Arch."},{"key":"2023072707434705400_bib4","doi-asserted-by":"publisher","first-page":"18397","DOI":"10.1038\/srep18397","article-title":"An engineered scorpion toxin analogue with improved Kv1. 3 selectivity displays reduced conformational flexibility","volume":"5","author":"Bartok","year":"2015","journal-title":"Sci. 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