Comparison of the crystal structures and intersubunit interactions of human immunodeficiency and Rous sarcoma virus proteases.

The crystal structures of the proteases (PRs) encoded by the Rous sarcoma virus (RSV) and the human immunodeficiency virus (HIV) have been compared. The crystallographic monomer of HIV PR superimposes on the two crystallographically independent subunits of the RSV PR dimer with root mean square deviations of 1.45 and 1.55 A for 86 and 88 common C alpha atoms, respectively. There is a conserved structural core consisting of seven beta-strands forming two perpendicular layers, a helix, and the amino- and carboxyl-terminal beta-strands. PRs from related retroviruses fold into similar structures with surface turns of variable length between the beta-strands. Both HIV and RSV PR dimers have significant subunit-subunit interactions in three regions: the "firemen's grip" at the active site; the salt bridges involving Arg8, Asp29, and Arg87 of HIV PR; and the termini of the two subunits, which form a four-stranded antiparallel beta-sheet. The specific interactions of the termini differ in the two PRs. The carboxyl termini, residues 96-99 of HIV PR and residues 119-124 of RSV PR, contribute approximately 50% of the intersubunit ionic and hydrogen bond interactions and approximately 45% of the buried surface area involved in dimer formation. This information may be useful in the design of site-directed mutations or inhibitors of dimer formation.