The monoclonal antibody 1696, directed against
the HIV-1 protease, displays strong inhibitory effects
toward the catalytic activity of the enzyme of both the
HIV-1 and HIV-2 isolates. This antibody cross-reacts with
peptides that include the N-terminus of the enzyme, a region
that is well conserved in sequence among different viral
strains and which, furthermore, is crucial for homodimerization
to the active enzymatic form. This observation, as well
as antigen-binding studies in the presence of an active
site inhibitor, suggest that 1696 inhibits the HIV protease
by destabilizing its active homodimeric form. To characterize
further how the antibody 1696 inhibits the HIV-1 and HIV-2
proteases, we have solved the crystal structure of its
Fab fragment by molecular replacement and refined it at
3.0 Å resolution. The antigen binding site has a
deep cavity at its center, which is lined mainly by acidic
and hydrophobic residues, and is large enough to accommodate
several antigen residues. The structure of the Fab 1696
could form a starting basis for the design of alternative
HIV protease-inhibiting molecules of broad specificity.