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Uncovering the structure of HIV-1 protease: why is it the key to antiviral treatment?
HIV-1 protease (HIV-1 PR) is a retroviral aspartic protease and an indispensable enzyme in the HIV life cycle. This enzyme is responsible for hydrolyzing polypeptide bonds and plays a key role in the transformation of HIV into mature viral particles. HIV-1 PR can cleave at nine cleavage sites in the newly synthesized polyprotein (mainly Gag and Gag-Pol) to generate mature HIV virus components, thereby making the HIV virus infectious.
Structure and Characteristics
The mature HIV protease is a 22 kDa homodimer, with each subunit consisting of 99 amino acids. Its active site is located between two identical subunits, and its characteristic catalytic triplet sequence is Asp-Thr-Gly (Asp25, Thr26 and Gly27), which is a common feature of aspartic proteases. HIV-1 PR can only act in the form of a dimer. The mature protease has two Asp25 amino acids, which are the catalytic residues provided by each monomer.
The protease has two molecular "flaps" that move up to 7 Å when the enzyme binds to its substrate, a process that can be visualized through animation.
Biosynthetic process
Precursor generation
HIV-1 PR is part of the Gag-Pol polyprotein, and its genetic code contains immature encoded proteins. PR as its precursor is located between reverse transcriptase (C-terminus of PR) and p6pol (N-terminus of PR). In order for this precursor to become a functional protein, each monomer must combine with another HIV-1 PR monomer to form an effective catalytically active site.
Synthesis mechanism
When HIV viral RNA enters the host cell, it is accompanied by reverse transcriptase, integrase and mature HIV-1 PR. Reverse transcriptase converts viral RNA into DNA, helping integrase embed the virus's genetic information into the host cell's DNA. Viral DNA can rest dormant in the nucleus or be transcribed into mRNA and translated into Gag-Pol polyprotein by the host cell, which is subsequently cleaved by mature HIV-1 PR to generate various functional proteins, including new HIV-1 PR. .
HIV-1 PR precursor catalyzes its own production through self-cleavage, a process called auto-processing. The process of self-processing can be divided into two sequential steps: first internal cleavage, then external cleavage, and finally the formation of the mature protease dimer.
Function and mechanism
HIV-1 PR is not just a precursor that catalyzes its own production. The mature protease can hydrolyze polypeptide bonds at nine specific sites in the Gag-Pol polyprotein, converting the generated subunits into components that are critical for HIV replication. Important functional proteins such as reverse transcriptase and integrase.
As a drug target
Due to the central role of HIV-1 PR in viral replication, this makes it a major target for antiviral drugs. HIV protease inhibitors specifically bind to the active site by mimicking the tetrahedral intermediate of the substrate, rendering the enzyme inactive.
Currently, the Food and Drug Administration has approved 10 HIV-1 PR inhibitors, including lidocide, saquinavir, ritonavir, etc. Although these inhibitors have different molecular components and mechanisms, they can all effectively interfere with the HIV replication process.
The evolution of drug resistance
Due to the extremely high mutation rate of retroviruses, the active site of HIV-1 PR may change rapidly, rendering inhibitors ineffective. The development of drug resistance mainly involves "major mutations" and "minor mutations".
In order to reduce the development of drug resistance in HIV, most treatments use a combination of multiple drugs to reduce the possibility of drug resistance by simultaneously inhibiting several key steps in HIV replication.
Conclusion
In summary, HIV-1 protease is not only crucial for HIV survival, but its structure and function also provide a rich research background for antiviral treatment. With a deeper understanding of its mechanism, it is possible to develop more effective treatments in the future. Let us wait and see whether this kind of progress can end the fight against AIDS?
