Inhibitor stabilization of human immunodeficiency virus type-2 proteinase dimer formation

We report the first direct observation of the subunit self-association behavior of highly purified recombinant human immunodeficiency virus type-2 (HIV-2) proteinase. Multiple samples of enzyme were subjected to sedimentation equilibrium analytical ultracentrifugation sequentially at 8.8 degrees C a...

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Bibliographic Details
Published in:The Journal of biological chemistry 1991-10, Vol.266 (29), p.19217-19220
Main Authors: HOLZMAN, T. F, KOHLBRENNER, W. E, WEIGL, D, RITTENHOUSE, J, KEMPF, D, ERICKSON, J
Format: Article
Language:English
Subjects:
AIDS/HIV
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
HIV Protease Inhibitors
HIV-2 - enzymology
Hydrogen-Ion Concentration
Hydrolases
Pyridines - pharmacology
Structure-Activity Relationship
Ultracentrifugation
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Summary:We report the first direct observation of the subunit self-association behavior of highly purified recombinant human immunodeficiency virus type-2 (HIV-2) proteinase. Multiple samples of enzyme were subjected to sedimentation equilibrium analytical ultracentrifugation sequentially at 8.8 degrees C and two pH values in the presence and absence of a C2 symmetric, peptidomimetic inhibitor. At both pH values the enzyme exhibited sedimentation equilibrium behavior which fit a monomer-dimer-tetramer model. In the absence of inhibitor, the apparent Kd for dimer formation was less than approximately 100 microM and the apparent Kd for the weaker dimer-tetramer association was greater than approximately 100 microM. In the presence of inhibitor, at either pH, dimer formation was more strongly favored as indicated by a approximately 5-14-fold decrease in the apparent Kd for dimer formation and a approximately 1.2-4-fold increase in the apparent Kd for tetramer formation. The enhanced formation of dimer and decrease in higher order self-associated forms in the presence of an inhibitor is consistent with inhibitor stabilization of an active dimer. The inhibitor-induced stabilization of the dimeric species is consistent with a model for substrate-induced formation of active proteinase dimers in virion assembly.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)54985-1