HIV protease
| HIV-1 Protease (Retropepsin) | |||||||||
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HIV-1 protease dimer in white and grey, with peptide substrate in black and active site aspartate side chains in red. (PDB: 1KJF)
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| Identifiers | |||||||||
| EC number | 3.4.23.16 | ||||||||
| CAS number | 144114-21-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / EGO | ||||||||
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| Search | |
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| PMC | articles |
| PubMed | articles |
| NCBI | proteins |
HIV-1 protease is a retroviral aspartyl protease (retropepsin) that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV protease cleaves newly synthesized polyproteins (namely, Gag and Gag-Pol) at the appropriate places to create the mature protein components of an infectious HIV virion. Without effective HIV protease, HIV virions remain uninfectious. Thus, mutation of HIV protease's active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells, making HIV protease inhibition the subject of considerable pharmaceutical research.
HIV protease's protein structure has been investigated using X-ray crystallography. It exists as a homodimer, with each subunit made up of 99 amino acids.
The active site lies between the identical subunits and has the characteristic Asp-Thr-Gly (Asp25, Thr26 and Gly27) sequence common to aspartic proteases. The two Asp25 residues (one from each chain) act as the catalytic residues. According to the mechanism for HIV protease protein cleavage proposed by Mariusz Jaskolski and colleagues, water acts as a nucleophile, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond. Additionally, HIV protease has two molecular "flaps" which move a distance of up to 7 Å when the enzyme becomes associated with a substrate.
With its integral role in HIV replication, HIV protease has been a prime target for drug therapy. HIV protease inhibitors work by specifically binding to the active site by mimicking the tetrahedral intermediate of its substrate and essentially becoming “stuck,” disabling the enzyme. After assembly and budding, viral particles lacking active protease cannot mature into infectious virions. Several protease inhibitors have been licensed for HIV therapy.
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