IDENTIFICATION OF A LOOP OUTSIDE THE ACTIVE-SITE CAVITY OF THE HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASES WHICH CONFERS INHIBITOR SPECIFICITY

We have investigated the inhibitor specificity for the proteases of th e human immunodeficiency viruses, types 1 and 2. Using a series of rel ated inhibitors, the P1' side chain was confirmed to play a significan t role in determining both the absolute and relative affinity for the enzymes. To further define the residues in the enzymes responsible for the difference in affinity, chimeric proteins were constructed in whi ch domains of the respective proteases were exchanged at the genetic l evel. The results of these studies demonstrated that inhibitor affinit y is conferred by a combination of the active site residues (32, 47, a nd 82) along with a loop comprised of residues 31 and 33-37, which lie s outside of the active site cavity. These results are discussed in te rms of existing structural data.