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 the human immunodeficiency viruses, types 1 and 2. Using a series of related inhibitors, the P1' side chain was confirmed to play a significant 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 which domains of the respective proteases were exchanged at the genetic level. The results of these studies demonstrated that inhibitor affinity is conferred by a combination of the active site residues (32, 47, and 82) along with a loop comprised of residues 31 and 33-37, which lies outside of the active site cavity. These results are discussed in terms of existing structural data.
Towler
E M
EM
Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Thompson
S K
SK
Tomaszek
T
T
Debouck
C
C
D000595:Amino Acid Sequence; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D015497:HIV-1; D015498:HIV-2; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D016333:HIV Protease