HIV-1 protease

HIV-1 Protease (Retropepsin)
File:Aspartic protease.png HIV-1 protease dimer in white and grey, with peptide substrate in black and active site aspartate side chains in red. (PDB: 1KJF​)
Identifiers
EC number	3.4.23.16
CAS number	Template:CAS
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
Search 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 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.

Structure and function

File:Molecular bulldog face.png

HIV-1 protease labelled according to its resemblance to an English Bulldog or a fat cat. The blue and cyan-green ribbons depict the peptide backbone of a wild-type (1D4S) and a mutant (1KZK) structure, respectively.

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.

HIV-1 protease as a drug target

The HIV-1 protease dimer (green and cyan) with active site Asp-25 in red.

Complexed with a polypeptide substrate (magenta). (PDB: 1KJF​)

Complexed with inhibitor BEA369 (depicted as a sticks with carbon in white, nitrogen in blue, oxygen in red). (PDB: 1EBY​)

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.

File:HIV-1 Protease with Active Site.png

HIV-1 Protease has the classic AspThrGly of Aspartyl Proteases. These amino acids are located at position 25, 26, and 27, and are responsible for the catalytic activity.

However, due to the high mutation rates of retroviruses, and considering that changes to a few amino acids within HIV protease can render it much less visible to an inhibitor, the active site of this enzyme can change rapidly when under the selective pressure of replication-inhibiting drugs.

One approach to minimizing the development of drug-resistance in HIV is to administer a combination of drugs which inhibit several key aspects of the HIV replication cycle simultaneously, rather than one drug at a time. Other drug therapy targets include reverse transcriptase, virus attachment, membrane fusion, cDNA integration and virion assembly.

See also

• Management of HIV/AIDS
• Discovery and development of HIV-protease inhibitors

External links

• The MEROPS online database for peptidases and their inhibitors: A02.001
• Proteopedia HIV-1_protease - the HIV-1 protease structure in interactive 3D
• HIV-1 Protease at the US National Library of Medicine Medical Subject Headings (MeSH)