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 Å 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 Å 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 6.4×10⁻⁶ M. The structural details and binding data suggest that the inhibition of PLA₂ by aspirin is of pharmacological significance and part of its anti-inflammatory effects may be due to its binding with PLA₂.