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

Abstract

a b s t r a c tPhospholipase A 2 (PLA 2 ) is an important component in snake venoms. Here, an acidic PLA 2 , 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 (IP 3 R) and induces mouse aorta contraction. PAR-1, phospholipase C and IP 3 R inhibitors suppressed PA2-Vb-induced aorta contraction. The crystal structure reveals that PA2-Vb has the typical fold of most snake venom PLA 2 . 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.

Isolation and Characterization of A2-EPTX-Nsm1a, a Secretory Phospholipase A2 from Malaysian Spitting Cobra (Naja sumatrana) Venom

“…The presence of active sites is essential in PLA 2 catalytic action, with this activity dependent on calcium ions as a cofactor [62,63]. Function prediction using PROSITE indicates that A2-EPTX-Nsm1a is an Asp49 PLA2, a type of PLA 2 commonly found in snake venoms [10,27,64]. This aspartic active site is vital for the snake venom PLA 2 catalytic network with His48, Tyr52, and Tyr64 residues [65].…”

“…PLA 2 toxins isolated from elapid and viperid snake venoms have been reported to cause muscle necrosis [8][9][10][11][12][13][14][15][16], induction of inflammatory cytokines [9,12,15,[17][18][19][20][21], neurotoxicity [15,[22][23][24][25], edema [9,14,18,19,21], hypotension [26], vasoconstriction [27], hemolysis [28], pulmonary congestion [12], intraperitoneal bleeding [12], and acute kidney injury [29]. Some snake venom PLA 2 s have been reported to have potential therapeutic activities including anti-cancer [30][31][32][33][34][35], anti-angiogenic [36], antibacterial [37,38], antiparasite [39], antithrombotic [40], anticoagulant [8,12,28,…”

Secreted Phospholipases A2 - not just Enzymes: Revisited

“…(2) heparan sulphate proteoglycans (HSPGs); (3) integrins; (4) vascular endothelial growth factor receptors (VEGFRs); and (5) ion channels. Two new integral membrane sPLA 2 -BPs have been described recently, a G-protein-coupled receptor (GPCR), and cytochrome c oxidase (CCOX) [35,37]. CCOX is the only known intracellular membrane sPLA 2 -BP, as all of the other integral membrane sPLA 2 -BPs are located in the plasma membrane.…”

“…PA2-Vb is an acidic sPLA 2 from venom of the Chinese green tree viper (Trimeresurus stejnegeri), and it was shown to induce mouse aorta contraction independent of its enzymatic activity, by acting on a protease-activated receptor (PAR-1), which is a GPCR [35]. GPCRs are the largest and most diverse class of membrane receptors in eukaryotes, and their primary function is to transduce extracellular stimuli into intracellular signals, which lead to different cell responses.…”

“…The effects of sPLA 2 s on haemostasis have great potential for medical applications as well. The induction of vasoconstriction by PA2-Vb binding to PAR-1 makes PA2-Vb interesting for the development of new therapeutic approaches against hypertension, atherosclerosis and diabetes-related vascular problems [35]. Moreover, snake venom sPLA 2 s can induce strong anticoagulant effects through competitive binding to constituents of the prothrombinase complex, which suggests their great potential for the development of therapeutic procedures to attenuate or prevent blood-clot formation [108].…”