1.C.74 The Snake Cytotoxin (SCT) Family The Snake Cytotoxin (SCT) (the SwissProt Snake Toxin) Family is a huge family of cytotoxins produced in the venomous glands of various snakes. These proteins are usually 80-100 residues long and have a single N-terminal TMS. Cobra cardiotoxins induce membrane leakage and cell death. CTXA3 is the major cardiotoxin from Taiwan cobra venom. It is internalized into mitochondria. CTXA3 binds to sulfatides (sulfogalactosyl ceamides) in the plasma membrane and forms transmembrane beta-sheet pores. The structure of CTXA3 in complexation with sulfatides in a membrane-like environment has been solved to 2.3 Å resolution, and the mode of toxin insertion into the plasma membrane has been predicted (Wang et al., 2006). A lipid-mediated toxin translocation mechanism has been proposed (Wang et al., 2006). α-bungarotoxin, a homologue of cobra cardiotoxin, binds to and inhibits the acetylcholine receptor (TC #1.A.9). Its 3-dimensional structure is also known. Sulfatides induce CTX A3 oligomerization in sulfatide containing phosphatidylcholine (PC) vesicles to form transient pores with pore size and lifetime in the range of about 30 A and 10^-2 s, respectively (Tjong et al., 2007). Reorientation of sulfatide is needed for CTX A3 dimer formation. The reaction catalyzed by transporting snake toxins is: ions and small molecules (in) → ions and small molecules (out)
This family belongs to the Aerolysin Superfamily.
References:
Chien, K.Y., C.M. Chiang, Y.C. Hseu, A.A. Vyas, G.S. Rule, and W. Wu. (1994). Two distinct types of cardiotoxin as revealed by the structure and activity relationship of their interaction with zwitterionic phospholipid dispersions. J. Biol. Chem. 269: 14473-14483.
Maeda, S., J. Xu, F.M. N Kadji, M.J. Clark, J. Zhao, N. Tsutsumi, J. Aoki, R.K. Sunahara, A. Inoue, K.C. Garcia, and B.K. Kobilka. (2020). Structure and selectivity engineering of the M muscarinic receptor toxin complex. Science 369: 161-167.
Tjong, S.C., P.L. Wu, C.M Wang, W.N. Huang, N.L. Ho, and W.G. Wu. (2007). Role of glycosphingolipid conformational change in membrane pore forming activity of cobra cardiotoxin. Biochemistry. 46(43):12111-12123.
Wang, C.H., J.H. Liu, S.C. Lee, C.D. Hsiao, and W.G. Wu. (2006). Glycosphingolipid-facilitated membrane insertion and internalization of cobra cardiotoxin. The sulfatide.cardiotoxin complex structure in a membrane-like environment suggests a lipid-dependent cell-penetrating mechanism for membrane binding polypeptides. J. Biol. Chem. 281: 656-667.
Examples:
TC#	Name	Organismal Type	Example
1.C.74.1.1	Cobra cardiotoxin-1 (cytotoxin CM-6), CTX1. It is a basic protein that binds to cell membranes and depolarizes cardiomyocytes. It also possesses lytic activity on many cells, including red blood cells (Chien et al. 1994). Cytotoxicity is due to pore formation and to another mechanism independent of membrane-damaging activity (Wang et al. 2006).	Snakes	*CTX1 of Naja naja* (P60305)**

1.C.74.1.2	α-bungarotoxin isoform A31 (α-BTX A31) (blocks activity of the nicotinic acetylcholine receptor (TC #1.A.9)	Snakes	*αBTX A31 of Bungarus multicinctus* (P60615)**

1.C.74.1.3	β-cardiotoxin, CTX14, of 84 aas.	Snakes	CTX14 pf Ophiophagus hannah (King cobra) (Naja hannah)

1.C.74.1.4	Long neurotoxin 43, LNTX43 of 108 aa	Snakes	LNTX-43 of Drysdalia coronoides (White-lipped snake) (Hoplocephalus coronoides)

1.C.74.1.5	Bucain of 65 aas	Snakes	*Bucain of Bungarus candidus* (Malayan krait)**

1.C.74.1.6	3 finger muscarinic toxin, Mt1 of 66 aas. Shows a non-competitive interaction with adrenergic and muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC₅₀=2.3 nM), alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine receptors, probably by interacting with the orthosteric site.	Snakes	MT1 of Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps)

1.C.74.1.7	α-elapitoxin 2a, Nno2a of 73 aas	Snakes	Nno2a of Naja oxiana (Central Asian cobra) (Oxus cobra)

1.C.74.1.8	Muscarinic toxin MT7 of 88 aas and 1 TMS. Forms a complex with the M1 muscarinic receptor with subnanomorlar affinity with a very slow dissociation rate. The 3-D crystal structure is known and reveals how it inhibits agonist-mediated GTP-γ-S binding and downstream signaling (Maeda et al. 2020).		MT7 of Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps)

1.C.74.1.9	Cytotoxin 1f of 15 aas. It shows cytolytic activity on many different cells by forming a pore in lipid membranes. In vivo, it increases heart rate or kills the animal by cardiac arrest. In addition, it binds to heparin with high affinity, interacts with K_v channel-interacting protein 1 (KCNIP1) in a calcium-independent manner, and binds to integrin alpha-V/beta-3 (ITGAV/ITGB3) with moderate affinity.		Cytotoxin 1f of Naja atro (Chinese cobra)