Proc. Natl. Sci. Counc. ROC(A) Vol. 23, No. 1, 1999. pp. 1-19 (Invited Review Paper) Understanding the Structure, Function and Folding of Cobra Toxins THALLAMPURANAM KRISHNASWAMY SURESH KUMAR*, SHUNMUGIAH THEVAR KARUTHA PANDIAN*, GURUNATHAN JAYARAMAN*, HO-J EN PENG**, AND CHIN YU* , † *Department of Chemistry National Tsing Hua University Hsinchu, Taiwan, R.O.C. **Department of Medical Research Veterans General Hospital Taipei, Taiwan, R.O.C. (Received March 13, 1998; Accepted June 2, 1998) ABSTRACT Cardiotoxins and neurotoxins derived from cobra venoms are small molecular weight (6.5-9.0 kDa) homologous proteins with a high degree of disulfide crosslinking. The lethality of the cobra venoms are attributed to the cardio- and neurotoxins. The three-dimensional structures of the members of these two classes of toxins show striking resemblance. Both cardio- and neurotoxins are ‘three-finger’ shaped proteins with three loops projecting from a globular head. The secondary structural elements in both of the toxins include an antiparallel triple and a double stranded β-sheet. Interestingly, despite the fact that the overall topologies of their three-dimensional structures are similar, cardio- and neurotoxins show drastically different biological properties. The molecular basis for the differential functional properties of these two classes of toxins is still not clear. The aim of this comprehensive review is to summarize and critically evaluate recent progress in research on the structure, function and folding aspects of cobra venom cardio- and neurotoxins. Key Words: all β-sheet proteins, cobra toxins, folding, function, structure † To whom all correspondence should be addressed. biological properties. Neurotoxins act on the acetyl- choline receptor at the post-synaptic level of the neuro- muscular junction (Zinn-Justin et al ., 1992; Yang et al ., 1969). In contrast, cardiotoxins exhibit a wide array of biological activities, such as (1) depolarization and contraction of muscular cells, (2) prevention of platelet aggregation and (3) lysis of cells like eryth- rocytes, epithelial cells, fetal lung cells and certain types of tumour cells, such as Yoshida Sarcoma cells (Kumar et al ., 1997; Rees and Bilwes, 1993; Hinman et al ., 1987). In addition, snake venom cardiotoxins are also known to inhibit the activity of enzymes, such as the Na + , K + -ATPase and protein kinase C (Kuo et al ., 1983; Raynor et al ., 1991; Chiou et al ., 1993). It is still an enigma as to how and why snake venom neurotoxins and cardiotoxins, inspite of significant amino acid sequence similarities, exhibit entirely dis- similar functional properties. It is imperative that a detailed analysis of the structural features of these I. Introduction Venoms of snakes belonging to the Elapidae family are highly toxic and produce effects such as flabby paralysis and respiratory failure in higher animals (Dufton and Hider, 1983, 1991). Most often, these effects culminate in the death of the victim. The lethal effects of a snake bite are attributed to the presence of a variety of toxic principles in their venoms (Harvey, 1985). The most prominent of the lethal ingredients in the elapid venoms belong to the class of toxic polypeptides termed neurotoxins and cardiotoxins or cytotoxins (Kumar et al ., 1994, 1997). Chemically, these neurotoxins and cardiotoxins are highly homolo- gous (> 50% homology) proteins with identical posi- tioning of the disulfide bridges (Dufton and Hider, 1983; Yu et al., 1994). Interestingly, despite the high degree of homology among the members belonging to these toxin classes, they differ drastically in their - 1 -