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| - | < | + | ==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. | |
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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 == | ||
| - | + | 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 == | == 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 == | == 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 == | ||
| - | <scene name='75/752268/ | + | 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> | ||
| - | Researchers in Japan Successfully isolated lipoate Protein Ligase A from ''e.Coli'' and crystallized it in order to determine the structure. The team divided the protein into two main sections; a Larger N terminus section consisting of Amino Acids 1-244, and a smaller C terminal unit consisting of amino acids 253-337. There is a small segment of linker amino acids (245-252) that connect the two subunits. Researchers found that there is a space exposed to solution formed between these two subunit's, and this exposed portion is the active site to which lipoic acid binds. The sulfur and carbon ring of lipoic acid is held into place via hydrophobic interactions with Particular Leucine, Phenylalanine, and Alanine residues inside of the active site, as well as some non ring portions ofa serine side chain. The carboxylic acid on lipoate was determinedc to held in place by Hydrogen bonding formed with side chains of either Serine-72 or Arginine-140 (researchers saw both results in crystallized protein). Researchers hypothesized that other compounds similar to lipoate could bind to the active site because of the relatively weak forces that bind the substrate. In the crystalization experiment performed, the team was unable to determine the binding site of ATP on the enzyme, But their Data suggested that the serine-72 implicated in holding the carboxyl group of lipoate also plays an important role in catalyzing the reaction between ATP and lipoate. The resaerchers also state that this enzyme, as well as some homologs closely related to it, exhibit a potential ATP binding motif from Amino Acids 69-75. The researchers believe this portion can make both a positive charge and a space that allow the binding of ATP to the enzyme. | ||
| + | </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.
