Sandbox 645
From Proteopedia
(→HIV-1 Protease) |
|||
| Line 23: | Line 23: | ||
=='''Mechanism'''== | =='''Mechanism'''== | ||
| - | + | ||
[[Image:Mechanism aspartyl protease.png|500 px]] | [[Image:Mechanism aspartyl protease.png|500 px]] | ||
Mechanism for HIV-1 Protease | Mechanism for HIV-1 Protease | ||
Revision as of 07:40, 27 November 2012
HIV-1 Protease
IntroductionHIV -1 protease (HIV PR ) is a retroviral aspartyl protease that is derived from HIV-1, a lentivirus that is best characterized for its ability to lower host immunity by infecting CD4+ T lymphocytes, macrophages, and dendritic cells.[1] Aspartyl proteases are protease enzymes that utilize aspartate residue(s) for the catalysis of peptide substrates. Eukaryotic forms of these proteases include the , cathepsins and renins. While they have a two-domain structure, the retroviral aspartyl proteases are much smaller and homologous to a single domain of the eukaryotic aspartic proteases. HIV-1 protease is essential for the life cycle of HIV. The protease takes newly synthesized polyproteins and cleaves them by means of a hydrolysis reaction into the smaller mature protein components of the HIV virion.[2] These proteins are used to form the virion capsid that encases the viral genome. Effectively inhibiting HIV-1 protease will result in the inability for HIV to propagate as it will no longer have the ability to form complete virion units to infect new cells. The HIV PR, together with single stranded RNA (ssRNA), reverse transcriptase, integrase, and other viral factors, is found inside the HIV-1 virion.[3] 
Structure & FunctionStructure of HIV-1 Protease In the mid 1980's, the structure of HIV-1 Protease was hypothesized by Lawrence Pearl and William Taylor to consist of a single domain of the eukaryotic aspartic protease and function in the dimeric form. As NMR was not yet in use at this time, x-ray crystallography was implored but required a large quantity of large crystals. This was problematic as heavy atom derivatives had to be used to overcome the phase problems with this new structure and a considerable amount of protein was needed. Eventually these problems were overcome and the first images of HIV-1 protease where announced by the Merck group, who were most successful at large-scale protein purification and crystallization. Unlike most members of the aspartyl protease class, which generally exist as two domain monomers, HIV protease is a dimmer with two identical that are comprised of 99 amino acids. Each subunit donates the catalytic triad, Asp-Ser-Gly, The X-ray structure of HIV-1 protease reveals that it is composed of , each consisting of 99 amino acid residues. The subunits come together in such as way as to . This tunnel is of critical importance because the active site of the protease is located in its interior. The active site consists of , making it a member of the aspartyl protease family. The two Asp's are that activate a water molecule to hydrolytically cleave the polyprotein that binds in the tunnel.[5] You may be wondering how a polyprotein makes its way into the active-site tunnel, as the to admit it. The key is the two flexible flaps on the top of the tunnel that to enter the tunnel. The flaps , shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage. Function of HIV-1 Protease Mechanism
The mechanism most commonly accepted for the aspartyl proteases is a general acid-base mechanism involving the coordination of a water molecule between the two highly conserved aspartate residues which leads to hydrolysis. One of the aspartate residues induces activation of the water molecule by removing one of the protons. This allows the nucleophilic oxygen to attack the carbonyl carbon of the peptide and form a tetrahedral oxyanion intermediate. Rearrangement leads to the protonation of the scissile amide and thus cleavage. Applications & Research
There currently is no cure or vaccine against HIV. Researchers, however, have discovered treatments that can halt and even reverse the progression of AIDS, due in large part to our understanding of the structure of HIV-1 protease. (Invirase) was the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV protease by , preventing the binding of polyproteins. Its chemical structure mimics the tetrahedral intermediate of the hydrolytic reaction, thereby .[6] Saquinavir is essentially an uncleavable ligand, as indicated by the on binding saquinavir or a polypeptide . Other drugs used to treat HIV infection that inhibit include (Crixivan), (Norvir), and (Viracept). When a HIV virus infects an organism it tends to multiply within the body’s cells. The virus is then released to infect other cells. In this manner, the infection of HIV infects the newly made cells of the body. While the viruses are produced, proteins and enzymes used to manufacture the DNA in addition to other components of the virus are made. In this case, protease is that enzyme that is needed to bring the structural and enzymes of the virus together. Protease drugs are what could inhibit this virus.
Based on the crystal structure data and protein receptor ligand complexes studied, interatomic interactions that work on burying atoms and find the statistical preference for amino acid pairs. A free energy model of the receptor-ligand is formulated and helps in showing the interfacial interactions. The interaction strength of this model has a reliability of ±1.5 kcal/mol, which reveals the importance of atomic interaction to stabilize the receptor-ligand interface. The analysis of a binding motif of HIV-1 protease inhibitor complex shows the important contacts instead of the set of atoms.
 Saquinavir mesylate is a white to off-white, very fine powder with an aqueous solubility of 2.22 mg/mL at 25°C.
 Ritonavir has a molecular weight of 711.88. It is very soluble in water and in methanol.
 Ritonavir is soluble in isopropanol and practically insoluble in water.
 Nelfinavir is slightly soluble in water at pH ≤ 4 and completely soluble in methanol.
References
| ||||||||||||
