Abstract
Amyloid beta (A beta) polypeptide plays a key role in determining the state of protein aggregation in Alzheimer's disease. The hydrophobic C-terminal part of the A beta peptide is critical in triggering the transformation from alpha-helical to beta-sheet structure. We hypothesized that phospholipase A(2) (PLA(2)) may inhibit the aggregation of A beta peptide by interacting with the peptide and keeping the two peptide chains apart. In order to examine the nature of interactions between PLA(2) and A beta peptide, we prepared and crystallized complex of Naja naja sagittifera PLA(2) with the C-terminal hepta-peptide Val-Gly-Gly-Val-Val-Ile-Ala. The X-ray intensity data were collected to 2.04 angstrom resolution and the structure was determined by molecular replacement and refined to the crystallographic R factor of 0.186. The structural analysis revealed that the peptide binds to PLA(2) at the hydrophobic substrate binding cavity forming at least eight hydrogen bonds and approximately a two dozen Van der Waals interactions. The number and nature of interactions indicate that the affinity between PLA(2) and the hepta-peptide is greater than the affinity between two A beta peptide chains. Therefore, PLA(2) is proposed as a probable ligand to prevent the aggregation of A beta peptides.