Crystal structure of phospholipase PA2-Vb, a protease-activated receptor agonist from the Trimeresurus stejnegeri snake venom

FEBS Lett. 2014 Dec 20;588(24):4604-12. doi: 10.1016/j.febslet.2014.10.032. Epub 2014 Nov 4.

Abstract

Phospholipase A2 (PLA2) is an important component in snake venoms. Here, an acidic PLA2, designated PA2-Vb was isolated from the Trimeresurus stejnegeri snake venom. PA2-Vb acts on a protease-activated receptor (PAR-1) to evoke Ca(2+) release through the inositol 1,4,5-trisphosphate receptor (IP3R) and induces mouse aorta contraction. PAR-1, phospholipase C and IP3R inhibitors suppressed PA2-Vb-induced aorta contraction. The crystal structure reveals that PA2-Vb has the typical fold of most snake venom PLA2. Several PEG molecules bond to a positively charged pocket. The finding offers a novel pharmacological basis of the structure for investigating the PAR-1 receptor and suggests potential applications for PA2-Vb in the vascular system.

Keywords: Acidic phospholipase A(2); Ca(2+) release; Crystal structure; IP(3) receptor; Vasoconstrictor activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism
  • Crotalid Venoms / enzymology*
  • Crystallography, X-Ray
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Sequence Data
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Phospholipases A2 / chemistry*
  • Phospholipases A2 / isolation & purification
  • Phospholipases A2 / pharmacology*
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Receptors, Proteinase-Activated / agonists*
  • Trimeresurus*
  • Vasoconstriction / drug effects

Substances

  • Crotalid Venoms
  • Receptors, Proteinase-Activated
  • Phospholipases A2
  • Calcium