title: Inhibition of HIV protease activity by heterodimer formation.
abstract: The dimeric nature of the HIV protease has been exploited to devise a novel mode of inhibiting the enzyme. The use of defective monomers or nonidentical subunits to exchange with wild-type homodimers produces catalytically defective heterodimers. Incubation of the HIV1 or HIV2 protease with a 4-fold molar excess of an inactive mutant of HIV1 leads to 80 and 95% inhibition of enzyme activity, respectively. Incubating HIV1 and HIV2 proteases at a 1:5 ratio results in a 50% reduction of activity of the mixed enzymes. The HIV1/HIV2 heterodimer was identified by ion-exchange HPLC. The heterodimer may display a disordered dimer interface, thereby affecting the catalytic potential of the enzyme. This mechanism of inactivation is an example of a dominant negative mutation that can obliterate the activity of a naturally occurring multisubunit enzyme. Furthermore, it provides an alternative to active-site-directed inhibitors for the development of antiviral agents that target the dimeric interface of the HIV protease.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
authors.forename: L M
authors.initials: LM
authors.lastname: Babé
authors.forename: S
authors.initials: S
authors.lastname: Pichuantes
authors.forename: C S
authors.initials: CS
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000201:enzymology; D015498:HIV-2 / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010957:Plasmids; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D017320:HIV Protease Inhibitors; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase; D016333:HIV Protease