6pwh

Cystal structure of Myotoxin II from Bothrops moojeni co-crystallized with Varespladib (LY315920)

spinqualitylabelsall models 6pwh, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pwh is a 2 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 1.749Å Ligands: DMS, VRD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PA2H2_BOTMO Snake venom phospholipase A2 homolog that lack enzymatic activity. Displays myotoxin and edema-inducing activities. Publication Abstract from PubMed The World Health Organization recently listed snakebite envenoming as a Neglected Tropical Disease, proposing strategies to significantly reduce the global burden of this complex pathology by 2030. In this context, effective adjuvant treatments to complement conventional antivenom therapy based on inhibitory molecules for specific venom toxins have gained renewed interest. Varespladib (LY315920) is a synthetic molecule clinically tested to block inflammatory cascades of several diseases associated with elevated levels of secreted phospholipase A2 (sPLA2). Most recently, Varespladib was tested against several whole snake venoms and isolated PLA2 toxins, demonstrating potent inhibitory activity. Herein, we describe the first structural and functional study of the complex between Varespladib and a PLA2-like snake venom toxin (MjTX-II). In vitro and in vivo experiments showed this compound's capacity to inhibit the cytotoxic and myotoxic effects of MjTX-II from the medically important South American snake, Bothrops moojeni. Crystallographic and bioinformatics analyses revealed interactions of Varespladib with two specific regions of the toxin, suggesting inhibition occurs by physical blockage of its allosteric activation, preventing the alignment of its functional sites and, consequently, impairing its ability to disrupt membranes. Furthermore, based on the analysis of several crystallographic structures, a distinction between toxin activators and inhibitors is proposed. Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920).,Salvador GHM, Gomes AAS, Bryan-Quiros W, Fernandez J, Lewin MR, Gutierrez JM, Lomonte B, Fontes MRM Sci Rep. 2019 Nov 20;9(1):17203. doi: 10.1038/s41598-019-53755-5. PMID:31748642 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phospholipase A2 homolog

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