A cumulative specificity model for proteases from human immunodeficiency virus types 1 and 2, inferred from statistical analysis of an extended substrate data base

Statistical analysis of an expanded data base of regions in viral polyproteins and in non-viral proteins that are sensitive to hydrolysis by the protease from human immunodeficiency virus (HIV) type 1 has generated a model which characterizes the substrate specificity of this retroviral enzyme. The...

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Bibliographic Details
Published in:The Journal of biological chemistry 1991-08, Vol.266 (22), p.14554-14561
Main Authors: POORMAN, R. A, TOMASSELLI, A. G, HEINRIKSON, R. L, KEZDY, F. J
Format: Article
Language:English
Subjects:
Actins - metabolism
AIDS/HIV
Algorithms
Amino Acid Sequence
Analytical, structural and metabolic biochemistry
Binding Sites
Biological and medical sciences
Calmodulin - metabolism
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
HIV Protease - metabolism
HIV-1 - enzymology
HIV-2 - enzymology
human immunodeficiency virus 2
Hydrolases
Information Systems
inhibitors
Models, Biological
Molecular Sequence Data
proteins
Substrate Specificity
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Summary:Statistical analysis of an expanded data base of regions in viral polyproteins and in non-viral proteins that are sensitive to hydrolysis by the protease from human immunodeficiency virus (HIV) type 1 has generated a model which characterizes the substrate specificity of this retroviral enzyme. The model leads to an algorithm for predicting protease-susceptible sites from primary structure. Amino acids in each of the sites from P4 to P4' are tabulated for 40 protein substrates, and the frequency of occurrence for each residue is compared to the natural abundance of that amino acid in a selected data set of globular proteins. The results suggest that the highest stringency for particular amino acid residues is at the P2, P1, and P2' positions of the substrate. The broad specificity of the HIV-1 protease appears to be a consequence of its being able to bind productively substrates in which interactions with only a few Pi or Pi' side-chains need be optimized. The analysis, extended to 22 protein segments cleaved by the HIV-2 protease, delineates marked differences in specificity from that of the HIV-1 enzyme.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)98722-3