6CEG

Solution NMR structure of the omega conotoxin MoVIB from Conus moncuri

Summary for 6CEG

• Entry DOI: 10.2210/pdb6ceg/pdb
• NMR Information: BMRB: 30405
• Descriptor: conotoxin MoVIB (1 entity in total)
• Functional Keywords: conotoxin, omega-conotoxin, ca2+ channel inhbitor, toxin
• Biological source: Conus (Conus moncuri)
• Total number of polymer chains: 1
• Total formula weight: 3506.15

Authors

Rosengren, K.J. (deposition date: 2018-02-11, release date: 2018-03-07, Last modification date: 2025-04-02)

Primary citation

Sousa, S.R.,McArthur, J.R.,Brust, A.,Bhola, R.F.,Rosengren, K.J.,Ragnarsson, L.,Dutertre, S.,Alewood, P.F.,Christie, M.J.,Adams, D.J.,Vetter, I.,Lewis, R.J.
Novel analgesic omega-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides.
Sci Rep, 8:13397-13397, 2018

PubMed Abstract: Cone snails are a diverse group of predatory marine invertebrates that deploy remarkably complex venoms to rapidly paralyse worm, mollusc or fish prey. ω-Conotoxins are neurotoxic peptides from cone snail venoms that inhibit Ca2.2 voltage-gated calcium channel, demonstrating potential for pain management via intrathecal (IT) administration. Here, we isolated and characterized two novel ω-conotoxins, MoVIA and MoVIB from Conus moncuri, the first to be identified in vermivorous (worm-hunting) cone snails. MoVIA and MoVIB potently inhibited human Ca2.2 in fluorimetric assays and rat Ca2.2 in patch clamp studies, and both potently displaced radiolabeled ω-conotoxin GVIA (I-GVIA) from human SH-SY5Y cells and fish brain membranes (IC 2-9 pM). Intriguingly, an arginine at position 13 in MoVIA and MoVIB replaced the functionally critical tyrosine found in piscivorous ω-conotoxins. To investigate its role, we synthesized MoVIB-[R13Y] and MVIIA-[Y13R]. Interestingly, MVIIA-[Y13R] completely lost Ca2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous ω-conotoxins whereas tyrosine 13 is preferred in piscivorous ω-conotoxins. MoVIB reversed pain behavior in a rat neuropathic pain model, confirming that vermivorous cone snails are a new source of analgesic ω-conotoxins. Given vermivorous cone snails are ancestral to piscivorous species, our findings support the repurposing of defensive venom peptides in the evolution of piscivorous Conidae.

PubMed: 30194442
DOI: 10.1038/s41598-018-31245-4

Experimental method

SOLUTION NMR