7lye

From Proteopedia

Myotoxin I from Bothrops moojeni co-crystallized with synthetic inhibitor Varespladib (LY315920)

PDB ID 7lye

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Structural highlights

7lye is a 4 chain structure with sequence from Bothrops moojeni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.758Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PA2H1_BOTMO Snake venom phospholipase A2 homolog that displays local myotoxin and edema-inducing activities and is lethal by intraperitoneal injection.^[1]

Publication Abstract from PubMed

BACKGROUND: The treatment for snakebites is early administration of antivenom, which can be highly effective in inhibiting the systemic effects of snake venoms, but is less effective in the treatment of extra-circulatory and local effects. To complement standard-of-care treatments such as antibody-based antivenoms, natural and synthetic small molecules have been proposed for the inhibition of key venom components such as phospholipase A2 (PLA2) and PLA2-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLA2s. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA2 and PLA2-like toxins. METHODS: In vivo and in vitro techniques were used to evaluate the inhibitory effect of varespladib against MjTX-I. X-ray crystallography was used to reveal details of the interaction between these molecules. A new methodology that combines crystallography, mass spectroscopy and phylogenetic data was used to review its primary sequence. RESULTS: Varespladib was able to inhibit the myotoxic and cytotoxic effects of MjTX-I. Structural analysis revealed a particular inhibitory mechanism of MjTX-I when compared to other PLA2-like myotoxin, presenting an oligomeric-independent function. CONCLUSION: Results suggest the effectiveness of varespladib for the inhibition of MjTX-I, in similarity with other PLA2 and PLA2-like toxins. GENERAL SIGNIFICANCE: Varespladib appears to be a promissory molecule in the treatment of local effects led by PLA2 and PLA2-like toxins (oligomeric dependent and independent), indicating that this is a multifunctional or broadly specific inhibitor for different toxins within this superfamily.

The synthetic varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxins.,Salvador GHM, Borges RJ, Lomonte B, Lewin MR, Fontes MRM Biochim Biophys Acta Gen Subj. 2021 Jul;1865(7):129913. doi:, 10.1016/j.bbagen.2021.129913. Epub 2021 Apr 16. PMID:33865953^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Soares AM, Andriao-Escarso SH, Angulo Y, Lomonte B, Gutierrez JM, Marangoni S, Toyama MH, Arni RK, Giglio JR. Structural and functional characterization of myotoxin I, a Lys49 phospholipase A(2) homologue from Bothrops moojeni (Caissaca) snake venom. Arch Biochem Biophys. 2000 Jan 1;373(1):7-15. PMID:10620318 doi:http://dx.doi.org/10.1006/abbi.1999.1492
↑ Salvador GHM, Borges RJ, Lomonte B, Lewin MR, Fontes MRM. The synthetic varespladib molecule is a multi-functional inhibitor for PLA(2) and PLA(2)-like ophidic toxins. Biochim Biophys Acta Gen Subj. 2021 Jul;1865(7):129913. PMID:33865953 doi:10.1016/j.bbagen.2021.129913