Aspirin induces its anti-inflammatory effects through its specific binding to phospholipase A2: crystal structure of the complex formed between phospholipase A2 and aspirin at 1.9 angstroms resolution.

Phospholipase A2 is potentially an important target for structure-based rational drug design. In order to determine the involvement of phospholipase A2 in the action of non-steroidal anti-inflammatory drugs (NSAIDs), the crystal structure of the complex formed between phospholipase A2 and aspirin has been determined at 1.9 angstroms resolution. The structure contains 915 protein atoms, 1 calcium ion, 13 atoms of aspirin and 105 water molecules. The observed electron density of the aspirin molecule in the structure was of very high quality thus allowing the precise determination of its atomic coordinates leading to the clear description of its interactions with the enzyme. The structure of the complex clearly shows that aspirin is literally embedded in the hydrophobic environment of PLA2. It is so placed in the substrate binding channel that it forms several important attractive interactions with calcium ion, His 48 and Asp 49. Thus, the structure of the complex clearly shows that aspirin occupies a favourable place in the specific binding site of PLA2. The binding studies have shown that acetyl salicylate (aspirin) binds to PLA2 enzyme specifically with a dissociation constant of 6.4 x 10(-6) M. The structural details and binding data suggest that the inhibition of PLA2 by aspirin is of pharmacological