In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition

Cardoso, Filomena; Souza, Maximilia F. de; Oliveira, Cristiano L. P.; Fontes, Marcos R.M.

doi:10.1016/j.biochi.2020.12.008

Cited by 8 publications

(1 citation statement)

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“…The basic residues (LYS0019, LYS0115, and ARG0118) of the membrane-docking site (MDoS) promote protein–membrane binding, while the hydrophobic ones (LEU0122, PRO0125, and PHE0126), located at the membrane-disrupting site (MDiS), induce membrane destabilization, consequently resulting in cell death , (see Figure b). Thus, in order to avoid recognition of the membrane, a number of compounds that bind MDoS and/or MDiS have been proposed. ,,− Among these, varespladib is a synthetic inhibitor of human-secreted group IIA PLA 2 , capable of inhibiting PLA 2 enzymes . Based on homology between the human group IIA PLA 2 and PLA 2 proteins found in snake venoms, varespladib was tested in a large panel of toxins and presented potent inhibition against PLA 2 activity .…”

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confidence: 99%

Quantum Biochemical Investigation of Lys49-PLA₂ from Bothrops moojeni

et al. 2021

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Envenomation via snakebites occurs largely in areas where it is harder to access the hospital. Its mortality rate and sequelae acquired by the survivors symbolize a big challenge for antivenom therapy. In particular, the homologous phospholipase A 2 (Lys49-PLA 2 ) proteins can induce myonecrosis and are not effectively neutralized by current treatments. Thus, by taking advantage of crystallographic structures of Bothrops moojeni Lys49-PLA 2 complexed with VRD (varespladib) and AIN (aspirin), a quantum biochemistry study based on the molecular fractionation with conjugate cap scheme within the density functional theory formalism is performed to unveil these complexes' detailed interaction energies. The calculations revealed that important interactions between ligands and the Lys49-PLA 2 pocket could occur up to a pocket radius of r = 6.5 (5.0 Å) for VRD (AIN), with the total interaction energy of the VRD ligand being higher than that of the AIN ligand, which is well-correlated with the experimental binding affinity. Furthermore, we have identified the role played by the amino acids LYS0069,

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