{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:18:49Z","timestamp":1781104729397,"version":"3.54.1"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,5,28]]},"abstract":"<jats:p>\n                    We recently reported the isolation of a scorpion toxin named U\n                    <jats:sub>1<\/jats:sub>\n                    -liotoxin-Lw1a (U\n                    <jats:sub>1<\/jats:sub>\n                    -LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U\n                    <jats:sub>1<\/jats:sub>\n                    -LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U\n                    <jats:sub>1<\/jats:sub>\n                    -LITX-Lw1a, now described as \u03c6-liotoxin-Lw1a (\u03c6-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of \u03c6-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. \u03c6-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1214062110","type":"journal-article","created":{"date-parts":[[2013,5,14]],"date-time":"2013-05-14T00:55:35Z","timestamp":1368492935000},"page":"8906-8911","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["Multiple actions of \u03c6-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins"],"prefix":"10.1073","volume":"110","author":[{"given":"Jennifer J.","family":"Smith","sequence":"first","affiliation":[{"name":"Chemical and Structural Biology, Institute for Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[{"name":"Chemical and Structural Biology, Institute for Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Chemical and Structural Biology, Institute for Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Peigneur","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Tytgat","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther M.","family":"Gallant","sequence":"additional","affiliation":[{"name":"Department of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A.","family":"Beard","sequence":"additional","affiliation":[{"name":"Discipline of Biomedical Sciences, Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT 2601, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Alewood","sequence":"additional","affiliation":[{"name":"Chemical and Structural Biology, Institute for Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela F.","family":"Dulhunty","sequence":"additional","affiliation":[{"name":"Department of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; 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