3-DIMENSIONAL STRUCTURES OF HIV-1 AND SIV PROTEASE PRODUCT COMPLEXES

Strain is eliminated as a factor in hydrolysis of the scissile peptide bond by human immunodeficiency virus (HIV)-1 and simian immunodeficie ncy virus (SIV), based on the first eight complexes of products of hyd rolysis with the enzymes. The carboxyl group generated at the scissile bond interacts with both catalytic aspartic acids. The structures dir ectly suggest the interactions of the gemdiol intermediate with the ac tive site. Based on the structures, the nucleophilic water is displace d stereospecifically by substrate binding toward one catalytic asparti c acid, while the scissile carbonyl becomes hydrogen bonded to the oth er catalytic aspartic acid in position for hydrolysis. Crystal structu res for two N-terminal (P) products and two C-terminal (Q) products pr ovide unambiguous density for the ligands at 2.2-2.6 Angstrom resoluti on and 17-21% R factors. The N-terminal product, Ac-S-L-N-F/, overlaps closely with the N-terminal sequences of peptidomimetic inhibitors bo und to the protease. Comparison of the two C-terminal products, /F-L-E -K and /F(NO2)-E-A-Nle-S, indicates that the P2' residue is highly con strained, while the positioning of the P1' and P3' residues are sequen ce dependent.