| 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.
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This family belongs to the Conotoxin Superfamily.
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| References: |
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.
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French, R.J. and H. Terlau. (2004). Sodium channel toxins–receptor targeting and therapeutic potential. Curr. Med. Chem. 11: 3053-3064.
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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.
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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.
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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.
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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.
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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.
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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.
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Robinson, S.D. and R.S. Norton. (2014). Conotoxin gene superfamilies. Mar Drugs 12: 6058-6101.
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Savarin, P., M. Guenneugues, B. Gilquin, H. Lamthanh, S. Gasparini, S. Zinn-Justin, and A. Ménez. (1998). Three-dimensional structure of kappa-conotoxin PVIIA, a novel potassium channel-blocking toxin from cone snails. Biochemistry 37: 5407-5416.
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Shon, K.J., M. Stocker, H. Terlau, W. Stühmer, R. Jacobsen, C. Walker, M. Grilley, M. Watkins, D.R. Hillyard, W.R. Gray, and B.M. Olivera. (1998). kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel. J. Biol. Chem. 273: 33-38.
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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.
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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.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.B.4.1.1 | Conotoxin, 33 aas
| Molluscs | Conotoxin of Conus ventricosus (cone snail) (P83301) |
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| 8.B.4.1.10 | Conotoxin of 80 aas and 1 TMS. | | Cx of Conus praecellens |
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| 8.B.4.1.11 | Omega-conotoxin Bu8 of 50 aas and 0 TMSs. Knottin; Neurotoxin; Secreted; Voltage-gated calcium channel impairing toxin. | | BuB toxin of Conus bullatus |
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| 8.B.4.1.12 | Delta conotoxin AtVIA, partial, of 30 aas and one TMS. | | δ-conotoxin, AtVIA of Conus ateralbus |
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| 8.B.4.1.13 | Conotoxin Superfamily T of 60 aas and 1 TMS
| | Conotoxin of Conus episcopatus |
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| 8.B.4.1.14 | T-2 (chi -or lambda-)conotoxin MrIA precursor (61aas) (inhibitor of the human norepinephrine transporter) (Lovelace et al., 2006). These toxins have a unique disulfide arrangement and folding pattern, and they contain 4-trans hydroxyproline (Balaji et al. 2000). | Molluscs | Conotoxin MrIA of Conus marmoreus (P58808) |
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| 8.B.4.1.15 | kappa-conotoxin PVIIA (Fin-popping peptide) of 72 aas. The three-dimensional structure has been solved. It is a potassium channel-blocking toxin from cone snails (Savarin et al. 1998). It blocks the activities of shaker K+ channels (Shon et al. 1998). | | kappa-conotoxin PVIIA of Conus purpurascens |
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| 8.B.4.1.2 | Conotoxin scaffold VI/VII precursor (CSP), 79 aas
| Molluscs | CSP of Conus pennaceus (AAG60403) |
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| 8.B.4.1.3 | Conopeptide precursor of 82 aas and 1 TMS. | Animals | Conopeptide precursor of Conus marmoreus (marble cone) |
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| 8.B.4.1.4 | O-superfamily conotoxin of 73 aas | Animals (Mollusca) | Conus toxin of Conus ebraeus
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| 8.B.4.1.5 | Huwentoxin-X or Ω-theraphotoxin-Hh1a of 68 aas. Voltage-gated Ca2+ channel blocker. The 3-d solution structure is known (Liu et al. 2006). | Spiders | Hwentoxin-X of Haplopelma schmidti (Selenocosmia huwena) |
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| 8.B.4.1.6 | U4-therophotoxin-Cj1a of 74 aas | Spiders | Therophotoxin of Chilobrachys guangxiensis (Chinese earth tiger tarantula) (Chilobrachys jingzhao) |
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| 8.B.4.1.7 | δ-conotoxin, TxVIA of 78 aas and 1 TMS. Binds to the extracellular sides of voltage-gated sodium
channels (Nav) and inhibits the inactivation process. Binding of this
toxin is calcium-dependent but not voltage-dependent. It is important in mollusks for the paralysis of prey. The 3-d solution structure is known (Kohno et al. 2002).
| | Conotoxin of Conus textile (Cloth-of-gold cone) |
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| 8.B.4.1.8 | Epsilon-conotoxin, TxVA, of 67 aas. ε-Conotoxins act at presynaptic membranes,
blocking calcium channels or G protein-coupled receptors. They causes hyperactivity upon intracranial injection into mice and dorsal fins
drooping in fish. | | ε-Conotoxin of Conus textile (Cloth-of-gold cone) |
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| 8.B.4.1.9 | Mu (μ)-conotoxin GVIIJ of 82 aas and 1 TMS. Mu-conotoxins block voltage-gated sodium channels
(Nav). This toxin (GVIIJ (SSG)) blocks Nav1.1/SCN1A (Kd=11 nM),
Nav1.2/SCN2A (Kd=11 nM), Nav1.3/SCN3A (Kd=15 nM), Nav1.4/SCN4A (Kd=4.7
nM), Nav1.6/SCN8A (Kd=360 nM) and Nav1.7/SCN9A (Kd=41 nM) (Gajewiak et al. 2014; Zhang et al. 2015). Coexpression of subunits beta-2 or beta-4 (but not beta-1 or beta-3) protects rNav1.1-1.7 against block by the toxin (Wilson et al. 2015).
| | Mu-conotoxin GVIIJ of Conus geographus (Geography cone) (Nubecula geographus) |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.B.4.3.1 | Conotoxin Ca5.1 precursor (71 aas and 2 TMSs) (Peng et al., 2007) | Cone Snails | Conotoxin Ca5.1 precursor of Conus caracteristicus (P0C666) |
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| 8.B.4.3.2 | Conotoxin of 60 aas and 1 TMS. | | Conotoxin of Conus andremenezi |
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| 8.B.4.3.3 | Conotoxin VnMLCL-03 of 65 aas and 2 TMSs. | | Conotoxin of Conus ventricosu |
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| 8.B.4.3.4 | Conotoxin T M1.17 of 71 aas and 1 TM | | Conotoxin of Conus magus |
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| Examples: |
| TC# | Name | Organismal Type | Example |