A Molecular Mechanism for Lys49-Phospholipase A2 Activity Based on Ligand-induced Conformational Change*

Agkistrodon contortrix laticinctus myotoxin is a Lys49-phospholipase A2 (EC 3.1.1.4) isolated from the venom of the serpent A. contortrix laticinctus (broad-banded copperhead). We present here three monomeric crystal structures of the myotoxin, obtained under different crystallization conditions. The three forms present notable structural differences and reveal that the presence of a ligand in the active site (naturally presumed to be a fatty acid) induces the exposure of a hydrophobic surface (the hydrophobic knuckle) toward the C terminus. The knuckle in A. contortrix laticinctus myotoxin involves the side chains of Phe121 and Phe124 and is a consequence of the formation of a canonical structure for the main chain within the region of residues 118–125. Comparison with other Lys49-phospholipase A2 myotoxins shows that although the knuckle is a generic structural motif common to all members of the family, it is not readily recognizable by simple sequence analyses. An activation mechanism is proposed that relates fatty acid retention at the active site to conformational changes within the C-terminal region, a part of the molecule that has long been associated with Ca2+-independent membrane damaging activity and myotoxicity. This provides, for the first time, a direct structural connection between the phospholipase “active site” and the C-terminal “myotoxic site,” justifying the otherwise enigmatic conservation of the residues of the former in supposedly catalytically inactive molecules.

• Publication year

  2005

• Venue

  Journal of Biological Chemistry

• Publication date

  2005-02-25

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M410588200PMID 15596433
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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