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A phage display library of 11,200 de novo proteins is designed using the \u03b1-KTx scaffold of 31 scorpion toxin sequences known or predicted to bind to potassium channels. Mokatoxin-1 (moka1) is isolated by affinity selection on purified target. Moka1 blocks Kv1.3 at nanomolar levels that do not inhibit Kv1.1, Kv1.2, or KCa1.1. As a result, moka1 suppresses CD3\/28-induced cytokine secretion by T cells without cross-reactive gastrointestinal hyperactivity. The 3D structure of moka1 rationalizes its specificity and validates the engineering approach, revealing a unique interaction surface supported on an \u03b1-KTx scaffold. This scaffold-based\/target-biased strategy overcomes many obstacles to production of selective toxins.<\/jats:p>","DOI":"10.1073\/pnas.0910123106","type":"journal-article","created":{"date-parts":[[2009,12,10]],"date-time":"2009-12-10T21:30:48Z","timestamp":1260480648000},"page":"22211-22216","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":74,"title":["A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library"],"prefix":"10.1073","volume":"106","author":[{"given":"Zoltan","family":"Takacs","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Institute of Molecular Pediatric Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Toups","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Institute of Molecular Pediatric Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Kollewe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Institute of Molecular Pediatric Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Institute of Molecular Pediatric Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis G.","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Driessens","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Biancalana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Koide","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano G.","family":"Ponte","sequence":"additional","affiliation":[{"name":"Coordena\u00e7\u00e3o de Biotecnologia, Instituto Federal do Rio de Janeiro, Rio de Janeiro, 20270-021, Brazil; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Perozo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Gajewski","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Suarez-Kurtz","sequence":"additional","affiliation":[{"name":"Divis\u00e3o de Farmacologia, Instituto Nacional de C\u00e2ncer, Rio de Janeiro, 20231-050, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Koide","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve A. 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