HIV-1 protease
Encyclopedia
HIV-1 protease is a retroviral aspartyl protease
that is essential for the life-cycle of HIV
, the retrovirus
that causes AIDS
.
HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion. Without effective HIV PR, HIV virions remain uninfectious.
Thus, mutation of HIV PR’s active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells,
making HIV PR inhibition the subject of much pharmaceutical research.
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 PR protein cleavage proposed by Jaskolski et al., water acts as a nucleophile
, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond.
Additionally, HIV PR has two molecular “flaps” which move a distance of up to 7 Å
when the enzyme becomes associated with a substrate.
s of retroviruses, and considering that a single amino acid change within HIV PR can render it invisible 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 drug cocktail
composed of drugs which inhibit several key aspects of HIV’s 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.
Retroviral aspartyl protease
Retroviral aspartyl proteases are single domain aspartyl proteases from retroviruses, retrotransposons, and badnaviruses . These proteases are generally part of a larger pol or gag polyprotein. Retroviral proteases are homologous to a single domain of the two-domain eukaryotic aspartyl proteases...
that is essential for the life-cycle of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, the retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
that causes AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion. Without effective HIV PR, HIV virions remain uninfectious.
Thus, mutation of HIV PR’s active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells,
making HIV PR inhibition the subject of much pharmaceutical research.
Structure and function
HIV PR's protein structureProtein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
has been investigated using X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
. 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
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-Thr
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
(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 PR protein cleavage proposed by Jaskolski et al., water acts as a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond.
Additionally, HIV PR has two molecular “flaps” which move a distance of up to 7 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
when the enzyme becomes associated with a substrate.
HIV-1 protease as a drug target
With its integral role in HIV replication, HIV PR has been a prime target for drug therapy. HIV PR inhibitors work by specifically binding to the active site by mimicking the tetrahedral intermediate of its substrate and essentially becoming “stuck,” disabling the enzyme. However, due to the high mutation rateMutation rate
In genetics, the mutation rate is the chance of a mutation occurring in an organism or gene in each generation...
s of retroviruses, and considering that a single amino acid change within HIV PR can render it invisible 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 drug cocktail
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
composed of drugs which inhibit several key aspects of HIV’s replication cycle simultaneously, rather than one drug at a time. Other drug therapy targets include reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, virus attachment, membrane fusion, cDNA integration and virion assembly.
External links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: A02.001 - the HIV-1 protease structure in interactive 3D