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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Babé LM,Pichuantes S,Craik CSdoi
10.1021/bi00215a016subject
Has Abstractpub_date
1991-01-08 00:00:00pages
106-11issue
1eissn
0006-2960issn
1520-4995journal_volume
30pub_type
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