Sandbox GGC4: Difference between revisions

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~~This is a default text for your page. Click above on '''edit this page''' to modify. Be careful with the < and > signs.~~

~~You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.~~

== 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 active site ~~of the protease~~. Usually, the active site consists of a triad (ASP-THR-GLY) on each monomer with the catalytic residue being D25.

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.

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 protease-inhibitor complex

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>.

== 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.

== 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>

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>

== 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.

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@@ Line 5: / Line 5: @@
 <StructureSection load='3VEV' size='340' side='right' caption='Caption for this structure' scene=''>
-This is a default text for your page. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
-You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
 == 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 active site of the protease. Usually, the active site consists of a triad (ASP-THR-GLY) on each monomer with the catalytic residue being D25.
+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.
-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 protease-inhibitor complex
+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>.
 == 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.
 == 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>,
+. <scene name='75/752268/Active_site_flap/1'>Active Site Flap of Mutated HIV-1 Protease</scene>,
+. <scene name='75/752268/Alpha-d-glucose/1'>Interaction with Alpha-D-glucose</scene>, and
+. <scene name='75/752268/Catalytic_residue_shift/1'>Catalytic Residue Shift
+</scene>
-This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 </StructureSection>
 == 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/>
+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.