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Modeling of acanthoxin A1, a PLA 2 enzyme from the venom of the common death adder ( Acanthophis antarcticus )
Author(s) -
Hains Peter G.,
Ramsland Paul A.,
Broady Kevin W.
Publication year - 1999
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19990401)35:1<80::aid-prot8>3.0.co;2-3
Subject(s) - enzyme , snake venom , chemistry , venom , active site , phospholipase a2 , stereochemistry , molecule , acceptor , binding site , biochemistry , organic chemistry , physics , condensed matter physics
The phospholipase A 2 enzyme, acanthoxin, found in the venom of the common death adder ( Acanthophis antarcticus ) as with other snake PLA 2 enzymes displays neurotoxic activity. It is unclear whether this neurotoxic activity particular to some snake PLA 2 enzymes is a result of structural differences solely within the catalytic sites or at a distant location upon the molecules. 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 high quality crystallographic structure, notexin was used as a molecular template 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 and nontoxic PLA 2 enzymes has led to a testable two‐step proposal of neurotoxic PLA 2 activity; involving the favorable binding to acceptor molecules followed by enzymatic intrusion upon the target membrane. The electrostatic potentials across the molecular surfaces of toxic and nontoxic PLA 2 enzymes were 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 potentially involved in the interaction of the PLA 2 enzymes with their acceptor molecules. Furthermore, the proposed acceptor molecule recognition site is distant from the catalytic site which upon binding of the PLA 2 to the acceptor molecule may enhance the enzymatic ability of the toxic PLA 2 enzymes on particular cell types. Proteins 1999;35:80–88. © 1999 Wiley‐Liss, Inc.