Modeling of acanthoxin A1, a PLA(2) enzyme from the venom of the common death adder (Acanthophis antarcticus)

The phospholipase A(2) enzyme, acanthoxin, found in the venom of the common death adder (Acanthophis antarcticus) as with other snake PLA(2) enzymes d isplays neurotoxic activity. It is unclear whether this neurotoxic activity particular to some snake PLA(2) enzymes is a result of structural differen ces solely within the catalytic sites or at a distant location upon the mol ecules. We have predicted the three-dimensional structure of one of the two predominant isoforms of acanthoxin (A1) using comparative protein modeling techniques. Given the high degree of homology and the availability of a hi gh quality crystallographic structure, notexin was used as a molecular temp late to construct an all atom model of acanthoxin. The model was made using the program MODELLER3 and then refined with X-PLOR. Comparison between the predicted structure of acanthoxin and several X-ray structures of toxic an d nontoxic PLA(2) enzymes has led to a testable two-step proposal of neurot oxic PLA(2) activity; involving the favorable binding to acceptor molecules followed by enzymatic intrusion upon the target membrane. The electrostati c potentials across the molecular surfaces of toxic and nontoxic PLA(2) enz ymes mere calculated (GRASP) and it was found that the toxic PLA(2) enzymes possessed a charge distribution on the noncatalytic surface not identified in the nontoxic PLA(2) enzymes. Thus we have identified residues potential ly involved in the interaction of the PLA(2) enzymes with their acceptor mo lecules. Furthermore, the proposed acceptor molecule recognition site is di stant from the catalytic site which upon binding of the PLA(2) to the accep tor molecule may enhance the enzymatic ability of the toxic PLA(2) enzymes on particular cell types. Proteins 1999 35:80-88. (C) 1999 Wiley-Liss, Inc.