8DND

Crystal structure of Bothrops pirajai Piratoxin-I (PrTX-I) and synthetic inhibitor Varespladib (LY315920)

Summary for 8DND

• Entry DOI: 10.2210/pdb8dnd/pdb
• Related: 2Q2J 6PWH 7LYE
• Descriptor: Basic phospholipase A2 homolog piratoxin-1, ({3-[amino(oxo)acetyl]-1-benzyl-2-ethyl-1H-indol-4-yl}oxy)acetic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: prtx-i, varespladib, bothrops pirajai, pla2-like toxin, toxin, toxin-antitoxin complex, toxin/antitoxin
• Biological source: Bothrops pirajai
• Total number of polymer chains: 2
• Total formula weight: 29033.64

Authors

Salvador, G.H.M.,Fontes, M.R.M. (deposition date: 2022-07-11, release date: 2023-08-02, Last modification date: 2024-10-30)

Primary citation

Salvador, G.H.M.,Pinto, E.K.R.,Ortolani, P.L.,Fortes-Dias, C.L.,Cavalcante, W.L.G.,Soares, A.M.,Lomonte, B.,Lewin, M.R.,Fontes, M.R.M.
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib.
Biochimie, 207:1-10, 2023

PubMed Abstract: Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A (PLA) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA. Recently, varespladib was also found to inhibit snake venom PLA and PLA-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA and PLA-like toxins.

PubMed: 36403756
DOI: 10.1016/j.biochi.2022.11.006

Experimental method

X-RAY DIFFRACTION (2.018 Å)