9Z5Y
Crystal structure of Bothrops pirajai myotoxin I PrTX-I complexed with inhibitor AZD2716
This is a non-PDB format compatible entry.
Summary for 9Z5Y
| Entry DOI | 10.2210/pdb9z5y/pdb |
| Descriptor | Basic phospholipase A2 homolog piratoxin-1, (2R)-3-[(1M)-5'-benzyl-2'-carbamoyl[1,1'-biphenyl]-3-yl]-2-methylpropanoic acid, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | bothrops pirajai, prtx-i, piratoxin i, phospholipase a2-like, azd2716, toxin |
| Biological source | Bothrops pirajai |
| Total number of polymer chains | 2 |
| Total formula weight | 28831.47 |
| Authors | |
| Primary citation | Salvador, G.H.M.,Pereira, E.S.,Cavalcante, W.L.G.,Ortolani, P.L.,Fortes-Dias, C.L.,Lomonte, B.,Lewin, M.R.,Fontes, M.R.M. Structural and pharmacological analysis of a PLA 2 -like toxin in complex with the sPLA 2 inhibitor AZD2716: Comparisons to varespladib. Biochimie, 245:120-131, 2026 Cited by PubMed Abstract: Phospholipase A (PLA) and PLA-like toxins are key contributors to the local myonecrotic effects induced by Bothrops snake venoms and represent important targets for inhibition. Synthetic molecules such as varespladib (LY315920) and AZD2716 were originally developed as inhibitors of human group IIA PLA, with varespladib emerging as a promising candidate for repurposing against venom toxins. Here, we investigated a snake venom Lys49-PLA-like toxin and another potent sPLA inhibitor, AZD2716, using ex vivo neuromuscular blockade assays, microscale thermophoresis, crystallographic, and bioinformatic analyses. Like varespladib, AZD2716 binds the toxin in the micromolar range within the hydrophobic channel (HCh)-which has been reported as the binding site for other inhibitors and fatty acids-adopting a dimeric conformation similar to that observed in other Lys49-PLA-like toxin complexes. Structural comparisons indicate that these ligands block access to HCh, preventing fatty acid binding required for toxin activation. The previously proposed mechanism of action for PLA-like toxins involves fatty acid binding to HCh, leading to conformational changes and solvent exposure of the toxin functional site, which is mainly located at the C-terminus. Thus, physically preventing fatty acid access to HCh can inhibit myotoxic activity. Although AZD2716 and varespladib bind to similar regions in both PLA-like toxins and catalytic sPLAs, they inhibit these proteins through distinct mechanisms due to differences in their functional sites. These findings highlight drug repurposing as a promising strategy for the development of complementary therapies to mitigate the severe local damage associated with snakebite envenoming but are generally applicable to drug discovery and repositioning strategies. PubMed: 41881275DOI: 10.1016/j.biochi.2026.03.006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
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