{
  "abstract": "Kv4 channels generate transient A-type potassium currents, but the contribution of Kv4.1 remains difficult to define because few pharmacological tools discriminate among Kv4 isoforms. We investigated the molecular basis of Kv4.1-selective inhibition by BlTx2, an α-KTx15 scorpion toxin from Buthacus leptochelys. Using electrophysiology, mutagenesis, tandem-channel analysis, structural modeling, and evolutionary analysis, we mapped the determinants governing BlTx2 activity and selectivity. Substitution of conserved α-KTx residues Lys27 and Tyr36 abolished detectable inhibition, whereas N30A reduced potency, supporting a canonical pore-blocking mechanism. A Kv4.1/Kv4.3 tandem chimera reduced BlTx2 potency, consistent with a contribution of adjacent Kv4.1 subunits to the high-affinity toxin-binding surface. Channel mutagenesis identified the Kv4.2/Kv4.3 lysine corresponding to Kv4.1 Asn355 as a key barrier to BlTx2 activity, since introducing this lysine into Kv4.1 abolished detectable inhibition. Mutational mapping of BlTx2 revealed that pore-facing residues required for inhibition are separated from peripheral residues that tune potency and cross-reactivity. In particular, Q9K and I18K conferred Kv1.2 activity, partly through interaction with Kv1.2 Glu355. Evolutionary analysis linked conserved pore-facing residues to purifying selection, and peripheral determinants to diversification. These findings identify distinct conserved and peripheral determinants that together shape BlTx2 activity and selectivity, thereby establishing BlTx2 as a useful probe for Kv4.1 function.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Life Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel.",
    "The Zelman Center for Brain Science Research, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuval Levy",
      "orcid": "0009-0003-4184-8673"
    },
    {
      "affs": [
        0
      ],
      "name": "Ayalon Reis"
    },
    {
      "affs": [
        0
      ],
      "name": "Galit Blecher",
      "orcid": "0009-0003-4678-5309"
    },
    {
      "affs": [
        0
      ],
      "name": "Oksana Daron"
    },
    {
      "affs": [
        0
      ],
      "name": "Sara Dadon"
    },
    {
      "affs": [
        0
      ],
      "name": "Raz Zarivach",
      "orcid": "0000-0001-6543-0296"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Noam Zilberberg",
      "orcid": "0000-0002-7848-2391"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9cyd1j7ndahnx.bib",
  "cited_by": 0,
  "doi": "10.3390/toxins18100431",
  "fulltext_url": "https://europepmc.org/articles/PMC13709427",
  "id": "9cyd1j7ndahnx",
  "issns": [
    "2072-6651"
  ],
  "landing_url": "https://europepmc.org/article/MED/42931522",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7221111290",
  "pdf_url": "https://europepmc.org/articles/PMC13709427?pdf=render",
  "pmcid": "PMC13709427",
  "pmid": "42931522",
  "published": "2026-10-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9cyd1j7ndahnx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:01Z",
      "native_id": "MED:42931522",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42931522"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ion channel regulation and function",
      "subfield": "molecular-biology"
    }
  ],
  "title": "The Architecture of Selectivity: Molecular Basis of BlTx2 Discrimination Among Kv Channels and Kv4 Isoforms.",
  "title_text": "The Architecture of Selectivity: Molecular Basis of BlTx2 Discrimination Among Kv Channels and Kv4 Isoforms.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:01Z",
  "url": "https://research.draconitic.com/paper/9cyd1j7ndahnx",
  "venue": "Toxins",
  "versions": []
}