Abstract
Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM-MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action.
Highlights
Phospholipase A2-like (PLA2-like) proteins, known as homologue-phospholipase A2 or K49-PLA2s, are widespread in the snake venom of Viperidae family members
PLA2-like proteins are small, with seven disulfide bridges and the following secondary structural elements: a N-terminal helix, putative calcium binding loop residues, two long antiparallel α-helices at the core of the protein that make up the hydrophobic channels, two antiparallel β-sheets known as β wings, one short 310 helix and C-terminal loop region
Analyzing the local and global measurements of available bothropic PLA2-like proteins, we identified two different states based on their roll angles: i) an inactive state that has an asymmetrical conformation with one non-canonical monomer and one hydrophobic channel accessible and ii) an active state with symmetrical canonical monomers and with both hydrophobic channels filled by hydrophobic molecules
Summary
Phospholipase A2-like (PLA2-like) proteins, known as homologue-phospholipase A2 or K49-PLA2s, are widespread in the snake venom of Viperidae family members. The PLA2-like structures in the inactive state only contain the accessible hydrophobic channel in monomers that are in the canonical conformation with a volume ~266 Å3 (Table 2).
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