Snake venom components in medicine: From the symbolic rod of Asclepius to tangible medical research and application.

Both mythologically and logically, snakes have always fascinated man. Snakes have attracted both awe and fear not only because of the elegant movement of their limbless bodies, but also because of the potency of their deadly venoms. Practically, in 2017, the world health organization (WHO) listed snake envenomation as a high priority neglected disease, as snakes inflict up to 2.7 million poisonous bites, around 100.000 casualties, and about three times as many invalidities on man. The venoms of poisonous snakes are a cocktail of potent compounds which specifically and avidly target numerous essential molecules with high efficacy. The individual effects of all venom toxins integrate into lethal dysfunctions of almost any organ system. It is this efficacy and specificity of each venom component, which after analysis of its structure and activity may serve as a potential lead structure for chemical imitation. Such toxin mimetics may help in influencing a specific body function pharmaceutically for the sake of man's health. In this review article, we will give some examples of snake venom components which have spurred the development of novel pharmaceutical compounds. Moreover, we will provide examples where such snake toxin-derived mimetics are in clinical use, trials, or consideration for further pharmaceutical exploitation, especially in the fields of hemostasis, thrombosis, coagulation, and metastasis. Thus, it becomes clear why a snake captured its symbolic place at the Asclepius rod with good reason still nowadays.

Correction: Dramatic and concerted conformational changes enable rhodocetin to block α2ß1 integrin selectively.

[This corrects the article DOI: 10.1371/journal.pbio.2001492.].

Dramatic and concerted conformational changes enable rhodocetin to block α2ß1 integrin selectively.

The collagen binding integrin α2ß1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αß and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2ß1 integrin. Besides the release of the nonbinding RCαß tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2ß1 integrin.

Influence of the operon structure on poly(3-hydroxypropionate) synthesis in Shimwellia blattae.

Glycerol has become a cheap and abundant carbon source due to biodiesel production at a large scale, and it is available for several biotechnological applications. We recently established poly(3-hydroxypropionate) [poly(3HP)] synthesis in a recombinant Shimwellia blattae strain (Heinrich et al. Appl Environ Microbiol 79:3582-3589, 2013). The major drawbacks of the current strains are (i) low poly(3HP) yields, (ii) low plasmid stability and (iii) insufficient conversion rates. In this study, we demonstrated the influence of alterations of the operon structure, consisting of 1,3-propanediol dehydrogenase (dhaT) and aldehyde dehydrogenase (aldD) of Pseudomonas putida KT2442, propionate:coenzyme A (propionate-CoA) transferase (pct) of Clostridium propionicum X2 and polyhydroxyalkanoate (PHA) synthase (phaC1) of Ralstonia eutropha H16. It was shown that S. blattae ATCC33430/pBBR1MCS-2::dhaT::pct::aldD::phaC1 synthesized up to 14.5 % (wtPHA/wtCDW) in a 2-L fed-batch fermentation process. Furthermore, we overcame the problem of plasmid losses during the fermentation period by engineering a carbon source-dependent plasmid addiction system in a triose phosphate isomerase knockout mutant. An assumed poly(3-hydroxyalkanoic acid) degrading activity of the lipase/esterase YbfF could not be confirmed.