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8.B.4 The Conotoxin T (Conotoxin T) Family

Numerous natural toxins have evolved to target sodium channels, either by blocking current through the pore or by modifying channel gating. Among the well studied toxins, the peptide conotoxins from cone snail venoms show a remarkable ability to discriminate among closely related forms of sodium channel, as well as exhibiting a variety of modes of action. The molecular basis of action of different Na channel targeted conotoxins have been reported, and their potential as models for the future design of more specifically targeted drugs have been explored (French and Terlau, 2004). Orientation of μ-conotoxin PIIIA in a sodium channel vestibule is based on the voltage dependence of its binding (McArthur et al., 2011).

One disulfide-rich conotoxin, MrIA, a 13-residue member of the -conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. Lovelace et al. (2006) showed that the β-hairpin structure of native MrIA is retained in a synthetic cyclic version, and is biological activity towards NET. The cyclic version has increased resistance to trypsin digestion relative to the native peptide. The increase in enzymatic stability against trypsin may be useful in improving the therapeutic potential of MrIA. The structure of cyclic MrIA (2J15_A) represents a new topology among a growing number of circular disulfide-rich peptides.

This family belongs to the: Conotoxin Superfamily.

References associated with 8.B.4 family:

Balaji, R.A., A. Ohtake, K. Sato, P. Gopalakrishnakone, R.M. Kini, K.T. Seow, and B.H. Bay. (2000). λ-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus. J. Biol. Chem. 275: 39516-39522. 10988292
French, R.J. and H. Terlau. (2004). Sodium channel toxins–receptor targeting and therapeutic potential. Curr. Med. Chem. 11: 3053-3064. 15578999
Gajewiak, J., L. Azam, J. Imperial, A. Walewska, B.R. Green, P.K. Bandyopadhyay, S. Raghuraman, B. Ueberheide, M. Bern, H.M. Zhou, N.A. Minassian, R.H. Hagan, M. Flinspach, Y. Liu, G. Bulaj, A.D. Wickenden, B.M. Olivera, D. Yoshikami, and M.M. Zhang. (2014). A disulfide tether stabilizes the block of sodium channels by the conotoxin μO§-GVIIJ. Proc. Natl. Acad. Sci. USA 111: 2758-2763. 24497506
Gorson, J., G. Ramrattan, A. Verdes, E.M. Wright, Y. Kantor, R. Rajaram Srinivasan, R. Musunuri, D. Packer, G. Albano, W.G. Qiu, and M. Holford. (2015). Molecular Diversity and Gene Evolution of the Venom Arsenal of Terebridae Predatory Marine Snails. Genome Biol Evol 7: 1761-1778. 26025559
Kohno, T., T. Sasaki, K. Kobayashi, M. Fainzilber, and K. Sato. (2002). Three-dimensional solution structure of the sodium channel agonist/antagonist δ-conotoxin TxVIA. J. Biol. Chem. 277: 36387-36391. 12145313
Lovelace, E.S., C.J. Armishaw, M.L. Colgrave, M.E. Wahlstrom, P.F. Alewood, N.L. Daly, and D.J. Craik. (2006). Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. J. Med. Chem. 49:6561-6568. 17064074
McArthur, J.R., G. Singh, M.L. O'Mara, D. McMaster, V. Ostroumov, D.P. Tieleman, and R.J. French. (2011). Orientation of μ-conotoxin PIIIA in a sodium channel vestibule, based on voltage dependence of its binding. Mol Pharmacol 80: 219-227. 21521769
Peng, C., X. Wu, Y. Han, D. Yuan, C. Chi, and C. Wang. (2007). Identification of six novel T-1 conotoxins from Conus pulicarius by molecular cloning. Peptides 28: 2116-2124. 17933431
Robinson, S.D. and R.S. Norton. (2014). Conotoxin gene superfamilies. Mar Drugs 12: 6058-6101. 25522317
Wilson, M.J., M.M. Zhang, J. Gajewiak, L. Azam, J.E. Rivier, B.M. Olivera, and D. Yoshikami. (2015). Α- and β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J Neurophysiol 113: 2289-2301. 25632083
Zhang, M.M., J. Gajewiak, L. Azam, G. Bulaj, B.M. Olivera, and D. Yoshikami. (2015). Probing the Redox States of Sodium Channel Cysteines at the Binding Site of μO§-Conotoxin GVIIJ. Biochemistry 54: 3911-3920. 26039939