Binding of acidic PLA2 Ba SpII RP4 from Bothrops alternatus snake venom to integrin αvβ3: an in silico study

LUCRECIA BOGADO; LEIVA, LAURA; EMILIO ANGELINA; MARÍA EMILIA GARCÍA DENEGRI; SOLEDAD BUSTILLO; NELIDA PERUCHENA

Buenos Aires

Congreso; 20th World Congress of the International Society on Toxinology; 2019

International Society on Toxinology

We have previously demonstrated that BaSpIIRP4 (an acidic PLA2 from Bothrops alternatus venom), enhance the endothelial cells (EC) detachment effect of a snake venom metalloproteinase. Considering that the binding of cells to their ligands depends on the interaction between extracellular matrix and integral membrane proteins, this effect may be due to interactions between PLA2 and EC integrins. The integrin alpha-v beta-3 (αvβ3) is commonly expressed in endothelial cells. It has been reported that human PLA2-IIA binds to this integrin with high affinity. Moreover, it was demonstrated that arginine residues R74 and R100 are critical for this binding. In addition, the interaction svPLA2-αvβ3 integrin was also described. Considering these previous findings about the interaction of human and snake venom PLA2-IIA with integrin αvβ3, in this work we use an in silico approach to predict whether BaSpIIRP4 would also bind to the same integrin, thus supporting the hypothesis that EC detachment could be a receptor-mediated effect. Since structure of BaSpIIRP4 PLA2 has not yet been elucidated, an enzyme homology model was built with the Modeller software. PLA2 from Bothrops jararacussu was selected as template structure. To identify putative sites on the surface of the PLA2 model with capacity to interact with the RGD site on the headpiece of the αvβ3 integrin, the protein-protein docking server ClusPro was employed. The stability of the identified anchoring points was evaluated by Molecular Dynamic simulations with Amber16 and binding free energy calculations with MM-PBSA protocol. Three interaction sites were found, one of them showing a strong resemblance with the previously identified site on human PLA2-IIA. These results suggest that integrin αvβ3 may serve as receptor for PLA2 from B. alternatus venom, and this interaction could be a novel therapeutic target.