Aspartic proteases immunodeficiency virus 1 protease

The human immunodeficiency virus protease (HIV-PR), an aspartic acid protease, is involved in the processing of viral polyproteins and is therefore essential for the production of new infectious virions. This enzyme is one of the best-characterized macromolecules from the vantage of drug design, with several hundred crystal structures determined to date. Protein crystallography has contributed in many... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Meek, Human immunodeficiency virus 1 protease expressed in Escherichia coli behaves as a dimeric aspartic protease, Proc. Natl. Acad. Sci. 86 9752 (1989). 

Retroviruses encode a protease (PR) responsible for cleaving polyprotein precursors, and such processing is essential for proper virion assembly and maturation. Based on the presence of a sequence Asp-Ser/Thr-Gly in the active sites of retroviral proteases (1) and their inhibition in vitro by pepstatin (2-7), these enzymes have been classified as members of the aspartic protease family. Crystal structures have been determined for the proteases from Rous sarcoma virus (RSV PR) (8), from two variants and several mutants of the human immunodeficiency vims (HIV PR) (9-11), from feline immunodeficiency virus (FIV PR) (12) and from equine infectious anemia vims (EIAV PR) (13). Aspartic proteases contain a single active site which includes two aspartates. In apoenzymes, the two catalytic Asp residues from the active site triad have been found to be in hydrogen bond contact with a water molecule (10). Mutations of the active site Asp25 in HIV-1 PR into Asn (14,15), Thr (3) or Ala (4,16,17) led to an inactive enzyme. Similarly, the RSV PR was inactivated by mutation of its active site Asp to He (18). 

Loeb, D. D., Hutchison, C. A., Edgell, M. H., Farmerie, W. G., and Swanstrom, R.(1989). Mutational analysis of human immunodeficiency virus type 1 protease suggests functional homology with aspartic proteinases. y. Virol. 63, 111-121. 

Hybrid potentials have been used to understand the mechanism of the human immunodeficiency virus (HIV) protease with the ultimate aim of being able to help in the design of inhibitors which could be useful as AIDS therapies. This enzyme, which catalyzes the hydrolysis of peptide bonds, is a homodimer. Its active center is at the interface of the two chains and consists of two catalytic aspartic acid residues from identical positions in each of the two chains. Although the aspartates are equivalent in the sequence, they are not equivalent when the substrate is present. It is known that when the enzyme is active one of the aspartic residues is protonated and it is thought that there is a lytic water molecule that is also involved in the catalysis. 

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