http://52.214.119.220/wiki/index.php?action=history&feed=atom&title=User%3ADan_Huettner%2FSandbox_1User:Dan Huettner/Sandbox 1 - Revision history2026-04-05T06:13:13ZRevision history for this page on the wikiMediaWiki 1.11.2http://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238169&oldid=prevDan Huettner at 21:41, 29 April 20112011-04-29T21:41:13Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins </scene></div></td><td colspan="2"> </td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238168&oldid=prevDan Huettner at 21:39, 29 April 20112011-04-29T21:39:01Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/3'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo <del style="color: red; font-weight: bold; text-decoration: none;">a </del><scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'><del style="color: red; font-weight: bold; text-decoration: none;">move to allow proteins </del></scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/3'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'><ins style="color: red; font-weight: bold; text-decoration: none;">dynamic conformation changes </ins></scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> For example, the inhibitor <scene name='User:Dan_Huettner/Sandbox_1/Inhibitor_indinavir/4'>Indinavir</scene> is shown to be tightly bounded in the active site of HIV-1 protease. These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease. Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> <del style="color: red; font-weight: bold; text-decoration: none;">The inhibitor <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir has multiple hydrogen bonding interactions, hyperstabilizing it into the active site. </scene> ([[1hsg]]) </del></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> For example, the inhibitor <scene name='User:Dan_Huettner/Sandbox_1/Inhibitor_indinavir/4'>Indinavir</scene> is shown to be tightly bounded in the active site of HIV-1 protease. These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease<ins style="color: red; font-weight: bold; text-decoration: none;">, as exemplified by the inhibitor <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir</ins>. <ins style="color: red; font-weight: bold; text-decoration: none;"></scene> ([[1hsg]]) </ins> Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> <ins style="color: red; font-weight: bold; text-decoration: none;"> </ins></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238165&oldid=prevDan Huettner at 21:33, 29 April 20112011-04-29T21:33:02Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/<del style="color: red; font-weight: bold; text-decoration: none;">2</del>'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins </scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/<ins style="color: red; font-weight: bold; text-decoration: none;">3</ins>'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins </scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> For example, the inhibitor <scene name='User:Dan_Huettner/Sandbox_1/Inhibitor_indinavir/<del style="color: red; font-weight: bold; text-decoration: none;">3</del>'>Indinavir</scene> is shown to be tightly bounded in the active site of HIV-1 protease. These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease. Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> The inhibitor <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir has multiple hydrogen bonding interactions, hyperstabilizing it into the active site. </scene> ([[1hsg]]) </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> For example, the inhibitor <scene name='User:Dan_Huettner/Sandbox_1/Inhibitor_indinavir/<ins style="color: red; font-weight: bold; text-decoration: none;">4</ins>'>Indinavir</scene> is shown to be tightly bounded in the active site of HIV-1 protease. These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease. Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> The inhibitor <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir has multiple hydrogen bonding interactions, hyperstabilizing it into the active site. </scene> ([[1hsg]]) </div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238162&oldid=prevDan Huettner at 21:27, 29 April 20112011-04-29T21:27:42Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/<del style="color: red; font-weight: bold; text-decoration: none;">1</del>'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'><del style="color: red; font-weight: bold; text-decoration: none;">dramatic conformational change </del></scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel.</scene><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/<ins style="color: red; font-weight: bold; text-decoration: none;">2</ins>'>normally too narrow</scene> for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'><ins style="color: red; font-weight: bold; text-decoration: none;">move to allow proteins </ins></scene> from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td></tr>
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</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238160&oldid=prevDan Huettner at 21:21, 29 April 20112011-04-29T21:21:56Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins </scene></div></td><td colspan="2"> </td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238159&oldid=prevDan Huettner at 21:21, 29 April 20112011-04-29T21:21:29Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The first structures of HIV-1 protease were reported in 1989 revealing its homodimeric structure consisting of two identical monomers, each made up of 99 amino acids residues, related by a two-fold axis of symmetry.<ref>Spinelli, S.; Liu, Q.Z.; Alzari, P.M.; Hirel, .PH.; & Poljak, R.J. (1991). The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie., 73(11), 1391-1396.</ref> The secondary structure of each monomer contains antiparallel beta-sheets and a single alpha-helix. Each monomer is stabilized in a hydrophobic core by aliphatic residues – open long-chain carbons structures, while the homodimer is stabilized by non-covalent and hydrophobic interactions of the side chains.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> </div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is normally too narrow for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a dramatic conformational change from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site<ins style="color: red; font-weight: bold; text-decoration: none;">, <scene name='User:Dan_Huettner/Sandbox_1/Tunnel_view/1'>creating a tunnel</ins>.<ins style="color: red; font-weight: bold; text-decoration: none;"></scene></ins><ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='User:Dan_Huettner/Sandbox_1/Tunnel_width/1'></ins>normally too narrow<ins style="color: red; font-weight: bold; text-decoration: none;"></scene> </ins>for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'></ins>dramatic conformational change <ins style="color: red; font-weight: bold; text-decoration: none;"></scene> </ins>from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>HIV-1 protease is an aspartyl protease, similar to pepsin, which contains two essential aspartate (Asp25) residues, one from each monomer, that play a key role in the enzyme’s catalytic function at the active site. Like all aspartyl protease, the active site of HIV contains a highly conserved catalytic triad of three amino acid residues, Asp25-Thr26-Gly27 (Aspartate-Threonine-Glycine).<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> Each monomer contributes a single Asp-Thr-Gly triad to the active site, amounting to six amino acids in the active site of HIV-1 protease. The active site triads are located in a loop whose structures are stabilized by a network of hydrogen bonds. It has been hypothesized that the role of the Thr26 residues is to stabilize the conformational state of the active site through hydrogen bonding forces with one another, also known as “fireman’s grip”.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> Moreover, the Gly27 residues function to accommodate and bind the substrate for subsequent attack by the Asp residues.<ref name="Thirteen">Mager, P. P. (2001). The active site of HIV-1 protease. Medicinal Research Reviews, 21(4), 348-353.</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>HIV-1 protease is an aspartyl protease, similar to pepsin, which contains <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='User:Dan_Huettner/Sandbox_1/Active_site_asp25/2'></ins>two essential aspartate (Asp25) residues,<ins style="color: red; font-weight: bold; text-decoration: none;"></scene> </ins>one from each monomer, that play a key role in the enzyme’s catalytic function at the active site. Like all aspartyl protease, the active site of HIV contains a highly conserved <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='User:Dan_Huettner/Sandbox_1/Activesitetriad/1'></ins>catalytic triad<ins style="color: red; font-weight: bold; text-decoration: none;"></scene> </ins>of three amino acid residues, Asp25-Thr26-Gly27 (Aspartate-Threonine-Glycine).<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> Each monomer contributes a single Asp-Thr-Gly triad to the active site, amounting to six amino acids in the active site of HIV-1 protease. The active site triads are located in a loop whose structures are stabilized by a network of hydrogen bonds. It has been hypothesized that the role of the Thr26 residues is to stabilize the conformational state of the active site through hydrogen bonding forces with one another, also known as “fireman’s grip”.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> Moreover, the Gly27 residues function to accommodate and bind the substrate for subsequent attack by the Asp residues.<ref name="Thirteen">Mager, P. P. (2001). The active site of HIV-1 protease. Medicinal Research Reviews, 21(4), 348-353.</ref></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The Asp25 residues are nearly coplanar and interactive directly with the substrate. Each Asp25, being negatively charged amino acids, holds a water molecule, crucial for catalysis, through hydrogen bonding.<ref name="Thirteen">Mager, P. P. (2001). The active site of HIV-1 protease. Medicinal Research Reviews, 21(4), 348-353.</ref> The Asp25 residues and water together cleave the substrate through a general acid/base hydrolysis reaction. The active site aspartyl residues assume opposite roles during catalysis.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> One Asp25 residue behaves like an acid, donating a proton to the carbonyl oxygen of the substrate, as the other Asp25 behaves like a base, accepting a proton from water. This promotes the nucleophilic attack by the water on the substrate, cleaving the peptide bond of the polyprotein.<ref>Prashar, V., Bihani, S., Das, A., Ferrer, J. L., & Hosur, M. (2009). Catalytic water co-existing with a product peptide in the active site of HIV-1 protease revealed by X-ray structure analysis. PloS One, 4(11), 7860. </ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The Asp25 residues are nearly coplanar and interactive directly with the substrate. Each Asp25, being negatively charged amino acids, holds a water molecule, crucial for catalysis, through hydrogen bonding.<ref name="Thirteen">Mager, P. P. (2001). The active site of HIV-1 protease. Medicinal Research Reviews, 21(4), 348-353.</ref> The Asp25 residues and water together cleave the substrate through a general acid/base hydrolysis reaction. The active site aspartyl residues assume opposite roles during catalysis.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> One Asp25 residue behaves like an acid, donating a proton to the carbonyl oxygen of the substrate, as the other Asp25 behaves like a base, accepting a proton from water. This promotes the nucleophilic attack by the water on the substrate, cleaving the peptide bond of the polyprotein.<ref>Prashar, V., Bihani, S., Das, A., Ferrer, J. L., & Hosur, M. (2009). Catalytic water co-existing with a product peptide in the active site of HIV-1 protease revealed by X-ray structure analysis. PloS One, 4(11), 7860. </ref></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The active site of HIV-1 protease has been one of the key targets for fighting HIV/AIDS. The drug inhibitors are highly stable mimickers of the polyproteins that cannot be cleaved by HIV-1 protease. They are able to bind with higher affinity than the polyprotein substrate. These drugs function as reversible inhibitors that compete with the usual substrate for the enzyme’s active site through competitive inhibition.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref></div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease. Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> <del style="color: red; font-weight: bold; text-decoration: none;"> Figure 6 shows an </del>inhibitor<del style="color: red; font-weight: bold; text-decoration: none;">, </del>Indinavir <del style="color: red; font-weight: bold; text-decoration: none;">(PDB 1HSG)</del>, <del style="color: red; font-weight: bold; text-decoration: none;">tightly bound to </del>the active site <del style="color: red; font-weight: bold; text-decoration: none;">of HIV-1 protease</del>. </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Presently, nine protease inhibitors have been approved for clinical treatment of HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir, and tipranavir.<ref name="Twelve">Castro, H. C., Abreu, P. A., Geraldo, R. B., Martins, R. C., dos Santos, R., Loureiro, N. I., Cabral, L.M., &Rodrigues, C. R. (2011). Looking at the proteases from a simple perspective. Journal of Molecular Recognition : JMR, 24(2), 165-181.</ref> <ins style="color: red; font-weight: bold; text-decoration: none;">For example, the inhibitor <scene name='User:Dan_Huettner/Sandbox_1/Inhibitor_indinavir/3'>Indinavir</scene> is shown to be tightly bounded in the active site of HIV-1 protease. </ins>These inhibitors are smaller in size to the intended peptide substrates. They contain a central hydroxyl group that mimics the tetrahedral reaction intermediate, interacting with the carboxyl groups of the Asp25 residues of the active site, increasing their affinity for protease. Additionally, all the inhibitors contain polar groups that create hydrogen bonding interactions with numerous other residues within the active site tunnel, which are mediated by a conserved water molecule.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> <ins style="color: red; font-weight: bold; text-decoration: none;">The </ins>inhibitor <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='User:David_Canner/Sandbox_HIV/</ins>Indinavir<ins style="color: red; font-weight: bold; text-decoration: none;">/2'>Indinavir has multiple hydrogen bonding interactions</ins>, <ins style="color: red; font-weight: bold; text-decoration: none;">hyperstabilizing it into </ins>the active site. <ins style="color: red; font-weight: bold; text-decoration: none;"></scene> ([[1hsg]]) </ins> </div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238143&oldid=prevDan Huettner at 20:03, 29 April 20112011-04-29T20:03:58Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the United States, the Center for Disease Control (CDC) first recognized AIDS during the summer of 1981.<ref>Gallo, Robert C. (2002). The early years of HIV/AIDS. Science, 298(5599), 1728-1730.</ref> Subsequently in 1983, the discovery of the sinister “AIDS virus” coined it as the human immunodeficiency virus (HIV). According to the 2010 UNAIDS Global Report, in 2009, there were 33.3 million people (adults and children) living with HIV, and 1.8 million AIDS related deaths that year, which leads to a deplorable grand total of roughly 30 million deaths due to AIDS since the HIV virus began ravaging the world.<ref>UNAIDS, World Health Organization (WHO). (2010). Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. Retrieved April 26, 2011.</ref> </div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===VIROLOGY===</div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Protease inhibitors have been fundamental components of treatment therapies for HIV/AIDS since 1995, when antiviral protease inhibitors were first approved for clinical use. The integration of protease inhibitors in drug therapy has been associated with successful therapeutic treatment of HIV/AIDS, significantly reducing AIDS mortality and morbidity.</div></td></tr>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>====REFERENCES===</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>====REFERENCES<ins style="color: red; font-weight: bold; text-decoration: none;">=</ins>===</div></td></tr>
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</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238137&oldid=prevDan Huettner at 18:11, 29 April 20112011-04-29T18:11:26Z<p></p>
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<tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;">{{STRUCTURE_1hsg | PDB</del>=<del style="color: red; font-weight: bold; text-decoration: none;">1hsg | SCENE</del>= <del style="color: red; font-weight: bold; text-decoration: none;"> }}</del></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><ins style="color: red; font-weight: bold; text-decoration: none;"><Structure load</ins>=<ins style="color: red; font-weight: bold; text-decoration: none;">'1HSG' size</ins>=<ins style="color: red; font-weight: bold; text-decoration: none;">'500' frame='true' align='right' caption='HIV-1 Protease' scene='Insert optional scene name here' /></ins></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===ASPARTYL PROTEASE MECHANISM===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===ASPARTYL PROTEASE MECHANISM===</div></td></tr>
</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238070&oldid=prevDan Huettner at 07:31, 29 April 20112011-04-29T07:31:53Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is normally too narrow for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a dramatic conformational change from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Flexible flaps form from an extended turn of a beta sheet (beta hairpin loop) that covers the active site.<ref name="Ten">Louis, J. M., Ishima, R., Torchia, D. A., & Weber, I. T. (2007). HIV-1 protease: Structure, dynamics, and inhibition. Advances in Pharmacology (San Diego, Calif.), 55, 261-298.</ref> Incidentally, the active site tunnel is normally too narrow for the polyprotein to fit. However, the solution is the two flexible protein flaps (amino acid resides 45-55 on each monomer) that can move to allow the peptide to enter the tunnel active site.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref> These flaps undergo a dramatic conformational change from open to closed states to bind the substrate in the proper conformation for catalytic cleavage. The highly flexible tips of the flaps are glycine rich, which curl inside the cleft as the tunnel expands, burying many hydrophobic residues and exposing electronegative active site, while widening the tunnel enough for the substrate to enter.<ref name="Eleven">Toth, G., & Borics, A. (2006). Flap opening mechanism of HIV-1 protease. Journal of Molecular Graphics & Modelling, 24(6), 465-474.</ref></div></td></tr>
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</table>Dan Huettnerhttp://52.214.119.220/wiki/index.php?title=User:Dan_Huettner/Sandbox_1&diff=1238069&oldid=prevDan Huettner at 07:22, 29 April 20112011-04-29T07:22:52Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Consequently, a therapeutic cure or an effective vaccine (complicated by the tendency of HIV to rapidly mutate) against HIV/AIDS has not yet been developed; therefore, the clinical management of HIV-1 infected people largely relies on antiretroviral therapy. Since the HIV retrovirus contains enzymes imperative for its life cycle that are unique from humans, these are potential inhibitory drug targets to treat infection and to prevent the progression to AIDS. The usual, most effective treatment for HIV infection is a cocktail of drugs that inhibit fusion of the virus and the key enzymes reverse transcriptase, integrase, and protease. This approach for treatment as a combination of drugs is known as highly active antiretroviral therapy (HAART), which has improved the lives of millions around the world who suffer from HIV/AIDS.<ref>Lu, X. F., & Chen, Z. W. (2010). The development of anti-HIV-1 drugs. Yao Xue Xue Bao = Acta Pharmaceutica Sinica, 45(2), 165-176. </ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Consequently, a therapeutic cure or an effective vaccine (complicated by the tendency of HIV to rapidly mutate) against HIV/AIDS has not yet been developed; therefore, the clinical management of HIV-1 infected people largely relies on antiretroviral therapy. Since the HIV retrovirus contains enzymes imperative for its life cycle that are unique from humans, these are potential inhibitory drug targets to treat infection and to prevent the progression to AIDS. The usual, most effective treatment for HIV infection is a cocktail of drugs that inhibit fusion of the virus and the key enzymes reverse transcriptase, integrase, and protease. This approach for treatment as a combination of drugs is known as highly active antiretroviral therapy (HAART), which has improved the lives of millions around the world who suffer from HIV/AIDS.<ref>Lu, X. F., & Chen, Z. W. (2010). The development of anti-HIV-1 drugs. Yao Xue Xue Bao = Acta Pharmaceutica Sinica, 45(2), 165-176. </ref></div></td></tr>
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<tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===STRUCTURE AND ACTIVE SITE OF HIV-1 PROTEASE===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===STRUCTURE AND ACTIVE SITE OF HIV-1 PROTEASE===</div></td></tr>
</table>Dan Huettner