Sandbox 9888: Difference between revisions

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== '''Remicade (Infliximab)''' ==

== Structure ==

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Remicade (Infliximab) is a chimeric IgG1 monoclonal antibody consisting of 597 amino acids, weighing 149,000 Daltons <ref>PMID:23504311</ref>. This chimeric monoclonal antibody is produced when the variable regions of a murine antibody (25%) is fused with the constant regions of a human antibody (75%) at the hinge region through a genetic engineering process <ref>PMID:17592358</ref>. Within the hinge region, intramolecular disulfide bonds stabilize the two fragment antigen binding regions (Fab) to the fragment crystallizable region (Fc). <scene name='74/744162/Variable_chains_hc/1'>Click here to view separated Fab and Fc regions</scene>. The Fab regions are comprised of both a heavy and light chain, while the Fc region consist of only a heavy chain. Located in the folded Vh and Ch domains of the heavy chain, amino acid residues Glu-1 to Thr-226 are found <ref>PMID:23504311</ref>. <scene name='74/744162/Heavy_chain/1'>The heavy chain region is highlighted here, and only (1 of 3) molecules are shown, for simplicity</scene>. In addition, the <scene name='74/744162/Light_chain/1'>light chain</scene> is composed of residues Asp-1 to Cys-214 that fold into the Vl and Cl domain <ref>PMID:23504311</ref>. The heavy and light chain at the N-terminus form the variable region that functions as a receptor binding site.

After intravenously injecting Infliximab, the p55 and p75 receptors (TNF-R?) on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites <ref> PMID: 17916444 </ref>. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces <ref>PMID:23504311</ref>. Specifically, TNF-α contributes to the stability by creating a hydrophobic interface through amino acid residues such as the <scene name='74/744162/Tyr_141_atom/1'>Tyr-141 side chain</scene> <ref>PMID:23504311</ref>. This interface is formed primarily by the C-D and E-F <scene name='74/744162/Loops_tnf/2'>loop residues</scene> connecting the antiparallel 8-stranded Beta sheets <ref>PMID:23504311</ref>. To view the loop residues of the full structure complex, <scene name='74/744162/Loops_tnf_3molecule/1'>click here</scene>. These favorable interactions are essential to the complex formed between TNF-α and infliximab Fab.

After intravenously injecting Infliximab, the p55 and p75 receptors (TNF-R?) on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites <ref> PMID: 17916444 </ref>. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces <ref>PMID:23504311</ref>. Specifically, TNF-α contributes to the stability by creating a hydrophobic interface <ref>PMID:2777790</ref> through amino acid residues such as the <scene name='74/744162/Tyr_141_atom/1'>Tyr-141 side chain</scene> <ref>PMID:23504311</ref>. This interface is formed primarily by the C-D and E-F <scene name='74/744162/Loops_tnf/2'>loop residues</scene> connecting the antiparallel 8-stranded Beta sheets <ref>PMID:23504311</ref>. To view the loop residues of the full structure complex, <scene name='74/744162/Loops_tnf_3molecule/1'>click here</scene>. These favorable interactions are essential to the complex formed between TNF-α and infliximab Fab.

== History of Remicade ==

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In determining the proper amount of how much of the drug should be injected, Remicade is able to sufficiently block TNF-α from interacting with the TNF receptors (TNFR) <ref>PMID:17916444</ref>. Thus, inhibiting the receptor from signaling production of IL-1 and IL-6, both of which are pro-inflammatory cytokines <ref>PMID:27100432</ref>. When this occurs, Remicade acts as a competitive inhibitor to TNF-R. If an adequate amount is introduced, the interface will be obstructed, thus preventing TNF-α from participating further in diseases.

Once the complex forms, it is stabilized by the amino acid residues Gln67–His73 and Gln102–Lys112 of the C-D and E-F loops <ref>PMID:23504311</ref>. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region of TNF. This arises when TNF-α is in its active form and exists as a trimer <ref>PMID:23504311</ref>. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.

Once the complex forms, it is stabilized by the amino acid residues <scene name='74/744162/Cdef_residues/1'>Gln67–His73 and Gln102–Lys112</scene> of the C-D and E-F loops <ref>PMID:23504311</ref>. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region of TNF. This arises when TNF-α is in its active form and exists as a trimer <ref>PMID:23504311</ref>. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.

== Diseases ==

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@@ Line 1: / Line 1: @@
 == '''Remicade (Infliximab)''' ==
-<StructureSection load='4g3y' size='340' side='right' caption='4g3y, Biological Assembly 1, Resolution 2.6Å' scene='74/744162/Bio_assembly_1/2'>
+<StructureSection load='4g3y' size='340' side='right' caption='4g3y, Biological Assembly 1, Resolution 2.6Å' scene='74/744162/Bio_assembly_1/3'>
 == Structure ==
@@ Line 6: / Line 6: @@
 Remicade (Infliximab) is a chimeric IgG1 monoclonal antibody consisting of 597 amino acids, weighing 149,000 Daltons <ref>PMID:23504311</ref>. This chimeric monoclonal antibody is produced when the variable regions of a murine antibody (25%)  is fused with the constant regions of a human antibody (75%) at the hinge region through a genetic engineering process <ref>PMID:17592358</ref>. Within the hinge region, intramolecular disulfide bonds stabilize the two fragment antigen binding regions (Fab) to the fragment crystallizable region (Fc). <scene name='74/744162/Variable_chains_hc/1'>Click here to view separated Fab and Fc regions</scene>. The Fab regions are comprised of both a heavy and light chain, while the Fc region consist of only a heavy chain. Located in the folded Vh and Ch domains of the heavy chain, amino acid residues Glu-1 to Thr-226 are found <ref>PMID:23504311</ref>. <scene name='74/744162/Heavy_chain/1'>The heavy chain region is highlighted here, and only (1 of 3) molecules are shown, for simplicity</scene>. In addition, the <scene name='74/744162/Light_chain/1'>light chain</scene> is composed of residues Asp-1 to Cys-214 that fold into the Vl and Cl domain <ref>PMID:23504311</ref>. The heavy and light chain at the N-terminus form the variable region that functions as a receptor binding site.
-After intravenously injecting Infliximab, the p55 and p75 receptors (TNF-R?) on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites <ref> PMID: 17916444 </ref>. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces <ref>PMID:23504311</ref>. Specifically, TNF-α contributes to the stability by creating a hydrophobic interface through amino acid residues such as the <scene name='74/744162/Tyr_141_atom/1'>Tyr-141 side chain</scene> <ref>PMID:23504311</ref>. This interface is formed primarily by the C-D and E-F <scene name='74/744162/Loops_tnf/2'>loop residues</scene> connecting the antiparallel 8-stranded Beta sheets <ref>PMID:23504311</ref>. To view the loop residues of the full structure complex, <scene name='74/744162/Loops_tnf_3molecule/1'>click here</scene>. These favorable interactions are essential to the complex formed between TNF-α and infliximab Fab.
+After intravenously injecting Infliximab, the p55 and p75 receptors (TNF-R?) on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites <ref> PMID: 17916444 </ref>. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces <ref>PMID:23504311</ref>. Specifically, TNF-α contributes to the stability by creating a hydrophobic interface <ref>PMID:2777790</ref> through amino acid residues such as the <scene name='74/744162/Tyr_141_atom/1'>Tyr-141 side chain</scene> <ref>PMID:23504311</ref>. This interface is formed primarily by the C-D and E-F <scene name='74/744162/Loops_tnf/2'>loop residues</scene> connecting the antiparallel 8-stranded Beta sheets <ref>PMID:23504311</ref>. To view the loop residues of the full structure complex, <scene name='74/744162/Loops_tnf_3molecule/1'>click here</scene>. These favorable interactions are essential to the complex formed between TNF-α and infliximab Fab.
 == History of Remicade ==
@@ Line 22: / Line 22: @@
 In determining the proper amount of how much of the drug should be injected, Remicade is able to sufficiently block TNF-α from interacting with the TNF receptors (TNFR) <ref>PMID:17916444</ref>. Thus, inhibiting the receptor from signaling production of IL-1 and IL-6, both of which are pro-inflammatory cytokines <ref>PMID:27100432</ref>. When this occurs, Remicade acts as a competitive inhibitor to TNF-R. If an adequate amount is introduced, the interface will be obstructed, thus preventing TNF-α from participating further in diseases.
-Once the complex forms, it is stabilized by the amino acid residues Gln67–His73 and Gln102–Lys112 of the C-D and E-F loops <ref>PMID:23504311</ref>. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region of TNF. This arises when TNF-α is in its active form and exists as a trimer <ref>PMID:23504311</ref>. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.
+Once the complex forms, it is stabilized by the amino acid residues <scene name='74/744162/Cdef_residues/1'>Gln67–His73 and Gln102–Lys112</scene> of the C-D and E-F loops <ref>PMID:23504311</ref>. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region of TNF. This arises when TNF-α is in its active form and exists as a trimer <ref>PMID:23504311</ref>. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.
 == Diseases ==