7px2 | pdb_00007px2
Conotoxin Mu8.1 from Conus mucronatus
Structural highlights
FunctionCON81_CONMM Modestly and reversibly inhibits Cav2.3/CACNA1E (IC(50)=5.8 uM) recombinantly expressed in HEK293 cells without affecting the voltage dependence of activation. In mouse DRG sensory neurons, modulates depolarization-induced calcium influx.[1] Publication Abstract from PubMedAnimal 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. Ca2+ 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+ (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. A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.,Hackney CM, Florez Salcedo P, Mueller E, Koch TL, Kjelgaard LD, Watkins M, Zachariassen LG, Tuelung PS, McArthur JR, Adams DJ, Kristensen AS, Olivera B, Finol-Urdaneta RK, Safavi-Hemami H, Morth JP, Ellgaard L PLoS Biol. 2023 Aug 3;21(8):e3002217. doi: 10.1371/journal.pbio.3002217. , eCollection 2023 Aug. PMID:37535677[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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