7PX2

Conotoxin Mu8.1 from Conus mucronatus

Summary for 7PX2

• Entry DOI: 10.2210/pdb7px2/pdb
• Descriptor: Conotoxin Mu8.1, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID (3 entities in total)
• Functional Keywords: conotoxin, toxin
• Biological source: Conus mucronatus
• Total number of polymer chains: 6
• Total formula weight: 62651.26

Authors

Mueller, E.,Hackney, C.,Ellgaard, L.,Morth, J.P. (deposition date: 2021-10-07, release date: 2022-11-16, Last modification date: 2024-11-06)

Primary citation

Hackney, C.M.,Florez Salcedo, P.,Mueller, E.,Koch, T.L.,Kjelgaard, L.D.,Watkins, M.,Zachariassen, L.,Tuelund, P.S.,McArthur, J.R.,Adams, D.J.,Kristensen, A.S.,Olivera, B.,Finol-Urdaneta, R.K.,Safavi-Hemami, H.,Morth, J.P.,Ellgaard, L.
A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.
Plos Biol., 21:e3002217-e3002217, 2023

PubMed Abstract: 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. 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.

PubMed: 37535677
DOI: 10.1371/journal.pbio.3002217

Experimental method

X-RAY DIFFRACTION (2.12 Å)