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Cooper Medical Research Foundation","doi-asserted-by":"publisher","award":["PG2019396"],"award-info":[{"award-number":["PG2019396"]}],"id":[{"id":"10.13039\/501100001061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health & Medical Research Council","doi-asserted-by":"crossref","award":["APP1072113"],"award-info":[{"award-number":["APP1072113"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K\n                    <jats:sup>+<\/jats:sup>\n                    (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3002217","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T13:51:12Z","timestamp":1691070672000},"page":"e3002217","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-0495","authenticated-orcid":true,"given":"Celeste M.","family":"Hackney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Fl\u00f3rez Salcedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Lund","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lau D.","family":"Kjelgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda G.","family":"Zachariassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernille S\u00f8nderby","family":"Tuelung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"McArthur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders S.","family":"Kristensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baldomero","family":"Olivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio K.","family":"Finol-Urdaneta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Safavi-Hemami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Preben","family":"Morth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7018-0137","authenticated-orcid":true,"given":"Lars","family":"Ellgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"issue":"4","key":"pbio.3002217.ref001","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tree.2012.10.020","article-title":"Complex cocktails: the evolutionary novelty of venoms","volume":"28","author":"NR Casewell","year":"2013","journal-title":"Trends Ecol Evol"},{"issue":"10","key":"pbio.3002217.ref002","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/nrd1197","article-title":"Therapeutic potential of venom peptides","volume":"2","author":"RJ Lewis","year":"2003","journal-title":"Nat Rev Drug Discov"},{"issue":"10","key":"pbio.3002217.ref003","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1080\/17460441.2021.1922386","article-title":"Advances in venom peptide drug discovery: where are we at and where are we heading?","volume":"16","author":"TB Smallwood","year":"2021","journal-title":"Expert Opin Drug Discov."},{"issue":"4","key":"pbio.3002217.ref004","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41573-020-00135-8","article-title":"Trends in peptide drug discovery.","volume":"20","author":"M Muttenthaler","year":"2021","journal-title":"Nat Rev Drug Discov."},{"issue":"5","key":"pbio.3002217.ref005","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1093\/molbev\/msy034","article-title":"Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution. 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