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| - | = | + | ==HIV-1 Protease== |
| - | <StructureSection load=' | + | An infection of the Human Immuno-deficiency Virus can cause Acquired Immunodeficiency Syndrome (AIDS). HIV attacks the CD4 T cells that are an essential part of the cell-mediated immune response, without which the immune system cannot fight against other infections or cancers, causing AIDS. There are currently 37 million people worldwide living with HIV/AIDS, with approximately 1 million new cases each year along with approximately 1 million deaths a year. |
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| + | Antiretroviral Therapy is one of the HIV treatments that is most effective as the combinations of different medicines reduce the viral load to become undetectable and non-transmissible and also allows the immune system to recuperate and increase the CD4 count. Protease Inhibitors are one of the FDA approved medicines that target the viral Aspartyl Protease to prevent the HIV from making more copies of itself. | ||
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| + | <StructureSection load='3VEV' size='340' side='right' caption='Caption for this structure' scene=''> | ||
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== Function == | == Function == | ||
| - | <scene name='75/752268/ | + | HIV-1 Aspartyl Proteases are homo-dimeric proteolytic enzymes, also known as endopeptidases that allow water molecules to act as nucleophiles during catalysis when activated by 2 aspartic acid residues that make up the <scene name='75/752268/Active_site_without_inhibitor/1'>active site</scene>. Usually, the active site consists of a triad (ASP-THR-GLY) on each monomer with the catalytic residue being D25. |
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| - | + | Aspartyl Protease cleaves the Gag and Gag-Pol polyproteins that encode for other structural proteins and enzymes crucial for viral maturation. Hence, HIV-1 Protease Inhibitors have been developed to inhibit the viral protease enzyme to prevent the production and release of mature, infectious HIV virions. Here is how an inhibitor binds to the protease to form a <scene name='75/752268/Hiv-1_protease-inhibitor/1'>HIV-1 protease-inhibitor complex</scene>. | |
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| + | == Disease == | ||
| + | Protease inhibitors along with reverse transcriptase inhibitors have been proven to be effective in reducing the viral load to slow the development of AIDS, however in recent years, mutations on the HIV-1 Protease have become a new challenge for researchers and pharmaceutical companies. Here is an image of a <scene name='75/752268/Mdr_protease_18_mutation/1'>multi-drug resistant HIV-1 Protease enzyme</scene> from a patient for whom the protease inhibitor regimen is no longer effective. The HIV-1 strain from this patient has 9 mutations per monomer. The ineffectiveness of the protease inhibitors can allow the viral load to increase and allow the progression of AIDS. | ||
| - | == | + | == Relevance == |
| - | + | Once again, if the structure of the protease enzyme changes due to mutations, the protease inhibitors will not be effective in preventing viral maturation. The relevance of these mutations can be seen in the active site expansion that takes place, especially at <scene name='75/752268/Mutations_v82a_and_i84v/1'>residue positions 82 and 84</scene>, among others. Here, it can be seen that the V82A and the I84V mutation causes the distance between the active site flap to become wider as the amino acid side chains become shorter. The change in the distance of amino acid 83,84,182 and 184 is approximately 1.5 A each in amino acid residues according to Logsdon et al, 2004.This conformational change reduces the binding affinity of the protease inhibitor to the active site. | |
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== Structural highlights == | == Structural highlights == | ||
| + | Other notable structural highlights include the 1. <scene name='75/752268/Inhibitor_binding_site_of_mut1/1'>Inhibitor Binding Site of Mutated HIV-1 Protease</scene>, | ||
| + | 2. <scene name='75/752268/Active_site_flap/1'>Active Site Flap of Mutated HIV-1 Protease</scene>, | ||
| + | 3. <scene name='75/752268/Alpha-d-glucose/1'>Interaction with Alpha-D-glucose</scene>, and | ||
| + | 4. <scene name='75/752268/Catalytic_residue_shift/1'>Catalytic Residue Shift | ||
| + | </scene> | ||
| - | Mitochondrial cytochrome c oxidase is an important aspect of an aerobic cellular respiration, in which the amount of dioxygen is reduced to form water during pumping of proton at the inner membrane of the mitochondrial. The structure shows an overall view of the mitochondrial cytochrome c oxidase. It consist of all proteins including the alpa protein, side chains and water except the nucleic acid. The ligand and non standard residues included in this structure are Magnesium ion, sodium ion,Heme a, Copper(ii) ion, Formyl group and Phosphothreonine.<scene name="75/752268/Intro1/2">Oxidize-Reduced Inter membrane side</scene> The second structure describes the oxidize state of the mitochondrial with limited side chains (A and B). All the proteins were been selected at the oxidized side of the structure but the main idea was to identify the heme a [HEA] of cytochrome c-oxidase which is the element that causes pumping of the proton. Again all proteins, all atoms with a limited residue numbers and limit chains of A and B for the oxidize side of the Cytochrome c oxidase were selected. The side chains and residues were labelled. Water was then added between residues [Y]440 and [Y]371, labeled it. The Aspartate residue (Asp-51) labeled in the oxidized state shows a proton-pumping occurring at that site and also an hydrogen bonding connection with the channels, where water molecules are located.<scene name='75/752268/Introduction_5b/1'>Heme a element and hydrogen bonding</scene> of the protein. The next scene shows the distance measured between the water and the residue [Ser]205, [Y]440 , and [Y]371 <scene name='75/752268/Introduction_5c/1'>Bond distances between HOH and limited residues </scene>. The final structure view describes about the Reduced state of the cytochrome c oxidase, the main focus was on the Copper (ii) ion [Cu] and the low-spin heme a [HEA] to the reduction site which is located on the inner membrane of the mitochondrial. The limited residues shown in this structure includes TGL, Sodium ion [NA], and Magnesium ion [MG] at the side chain N, which were labeled and the distance between CU and HEA were also measured<scene name='75/752268/Introduction_7/1'>Cu and Heme a Bond distance </scene> | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
| - | + | Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity. J Virol. 2004 Mar;78(6):3123-32. doi: 10.1128/jvi.78.6.3123-3132.2004. PMID: 14990731; PMCID: PMC354404. | |
<references/> | <references/> | ||
| + | Munshi S, Chen Z, Li Y, Olsen DB, Fraley ME, Hungate RW, Kuo LC. Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):1053-60. doi: 10.1107/s0907444998003588. PMID: 9757136. | ||
Current revision
HIV-1 Protease
An infection of the Human Immuno-deficiency Virus can cause Acquired Immunodeficiency Syndrome (AIDS). HIV attacks the CD4 T cells that are an essential part of the cell-mediated immune response, without which the immune system cannot fight against other infections or cancers, causing AIDS. There are currently 37 million people worldwide living with HIV/AIDS, with approximately 1 million new cases each year along with approximately 1 million deaths a year.
Antiretroviral Therapy is one of the HIV treatments that is most effective as the combinations of different medicines reduce the viral load to become undetectable and non-transmissible and also allows the immune system to recuperate and increase the CD4 count. Protease Inhibitors are one of the FDA approved medicines that target the viral Aspartyl Protease to prevent the HIV from making more copies of itself.
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References
Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity. J Virol. 2004 Mar;78(6):3123-32. doi: 10.1128/jvi.78.6.3123-3132.2004. PMID: 14990731; PMCID: PMC354404.
Munshi S, Chen Z, Li Y, Olsen DB, Fraley ME, Hungate RW, Kuo LC. Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):1053-60. doi: 10.1107/s0907444998003588. PMID: 9757136.
