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Venoms provide a rich source of pharmacologically active compounds that are of interest both as potential models for drug design and as probes of biochemical systems and pathways. The male platypus, Ornithorhyncus anatinus, has venomous spurs on its hind limbs that are primarily used in defense of breeding territories. Following a platypus envenomation, the victim experiences tissue swelling and severe pain that can last for weeks. Unlike snake and spider venoms that are used for immobilization and predigestion of prey the platypus venom is used only to ward off potential enemies. The components that have been characterized so far appear to have milder effects than their counterparts in other venoms. Since the action of these compounds is less extreme than other venom-derived agents, the components in platypus venom are attractive leads for drug discovery. The venom contains several distinct peptides, many of which are interesting targets for structural or biochemical studies. These include a novel class of defensin-like peptides (DLPs) whose biological function is currently unknown despite structural similarity in solution to known antimicrobial defensins. Many known defensins operate by pore formation or disruption of membranes.
Knowledge of the structure adopted by DLPs in a membrane environment rather than in isotropic solution may clarify their activity. A determination of the structures of membrane-complexed DLPs will be undertaken using SAS. This method will provide a reasonable starting point for establishing the function of these peptides and gaining a greater understanding of the many toxins that share this type of fold. This question is interesting from an evolutionary perspective, since these toxins are distinguished by low sequence homology and varying functions while being related by a common fold. Such studies may also be useful for drug discovery purposes, as the defensin/DLP fold could be used as a scaffold for specific functional peptides. As increasing numbers of antibiotic-resistant bacterial strains are discovered, novel antibacterial agents are needed. Even more valuable would be a more general understanding of antimicrobial activity in peptide toxins. Determining structural information about defensins and related peptide toxins in membrane environments is a step toward understanding how subtle changes in amino acid sequence can effect very specific biological activities.
The most physiologically active peptide so far characterized from platypus venom is the C-type natriuretic peptide OvCNP, a 39-residue peptide that has high amino acid sequence homology with other mammalian C-type natriuretic peptides. OvCNP can interact with biological tissues by forming voltage-gated, weakly cation-selective channels. A solution NMR study of OvCNP in aqueous solution and in SDS micelles has indicated that the peptide is mostly unstructured, but does contain a stable loop structure. It is an open question whether the pore formed by OvCNP consists of a single peptide molecule, or if the peptide oligomerizes, forming a multimeric pore. In addition to its ion-channel forming properties, OvCNP also interacts with natriuretic peptide receptors, which are involved in the regulation of blood pressure. More detailed knowledge of the interaction of CNP with its receptor could lead to a greater understanding of these pathways and possible routes to therapeutic intervention for hypertension.
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