Sandbox 34: Difference between revisions

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== Structure ==

Papain is a relatively simple enzyme. It consists of only one chain of 212 residues with three disulfide bonds, illustrated in yellow. The single chain is separated into <scene name='Sandbox_34/Subunitsrandl/1'>two domains</scene>: R is shown in purple, and L in gray. A cleft is formed in which the <scene name='Sandbox_34/2subuwithactivesite/4'>active site</scene>, consisting of cysteine-25, histidine-159, and asparagine-175, resides.<ref name="PDBSum" /> A <scene name='Sandbox_34/Rainbown-c/1'>Rainbow-C</scene> illustration of this shows, from the N-terminus in blue to the C-terminus in red, an easy means by which to track the residues through the molecule. Many hydrogen bonds exist throughout the molecule, holding it in its 3D conformation. These stabilizing bonds, represented in white, are present both in the <scene name='Sandbox_34/Pap_with_h-bonding_btwnbckbne/2'>backbone</scene>, and between <scene name='Sandbox_34/Pap_with_h-bonding_btwnsdchns/3'>residues</scene>.

Papain is a relatively simple enzyme. It consists of only one chain of 212 residues, with a secondary structure composed of 21%

<scene name='Sandbox_34/Betasheets/1'>beta sheets</scene> and 25% <scene name='Sandbox_34/Alphahelices/1'>alpha helices</scene>.<ref name="RSCB PDB">http://www.rcsb.org/pdb/explore/explore.do?structureId=9PAP</ref> It's tertiary structure has three disulfide bonds, illustrated in yellow, between Cys22 and Cys63, Cys56, and Cys 95,and Cys153 and Cys200. The single chain is separated into <scene name='Sandbox_34/Subunitsrandl/1'>two domains</scene>: R is shown in purple, and L in gray. A cleft is formed in which the <scene name='Sandbox_34/2subuwithactivesite/4'>active site</scene>, consisting of cysteine-25, histidine-159, and asparagine-175, resides.<ref name="PDBSum" /> A <scene name='Sandbox_34/Rainbown-c/1'>Rainbow-C</scene> illustration of this shows, from the N-terminus in blue to the C-terminus in red, an easy means by which to track the residues through the molecule. Many hydrogen bonds exist throughout the molecule, holding it in its 3D conformation. These stabilizing bonds, represented in white, are present both in the <scene name='Sandbox_34/Pap_with_h-bonding_btwnbckbne/2'>backbone</scene>, and between <scene name='Sandbox_34/Pap_with_h-bonding_btwnsdchns/3'>residues</scene>.

<scene name='Sandbox_34/Salt_bridges/5'>Salt bridges</scene> also strongly contribute to the stability of the protein structure. In this particular image, clarification of residue coordination is demonstrated by color: paired residues are shown in the same color, oxygen is shown in red, and nitrogen is shown in blue A modified cysteine residue with a sulfhydryl group, <scene name='Sandbox_34/9pap_sulfhydryl_group/1'>cysteine sulfonic acid</scene>, is necessary for the activity of the enzyme<ref>http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/analytical-enzymes/papain.html</ref> In 9PAP, the primary representation of papain used in this article, the sulfhydryl group has been oxidized. Papain contains many <scene name='Sandbox_34/Hydrophobicpolar/1'>hydrophobic and polar regions</scene>. The <scene name='Sandbox_34/Hydrophobic_residues/1'>hydrophobic residues</scene> are illustrated in gray, and the <scene name='Sandbox_34/Polar_residues/1'>polar residues</scene> are illustrated in magenta.

In a paper entitled, ''The Structure of Papain Refined at 1.65 A Resoltion'', Kamphuis et al. discovered interesting information on <scene name='Sandbox_34/All_bonding_shenanigans/1'>direct protein-protein contacts</scene> between molecules of papain in solution. These contacts, communicated in Table 7 of their paper, consist of nine hydrogen-bond connections and three ionic interactions. The strongest salt bridge exists between <scene name='Sandbox_34/Arg191asp140intraxn/2'>asparagine-140 and arginine-191</scene>.<ref name="Structure" />

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===Cathepsin L===

Cathepsin L is an endosomal cysteine protease that is believed to have both physiological and pathophysiological effects on the human body. It has been indicated not only in cancer, rhematoid arthritis, and osteo-arthritis, but its mechanism also appears similar to that of Ebola, SARS, and Leishmania. Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> An interesting inhibitor for cathepsin L developed using papain as the model protease is that of <scene name='Sandbox_34/Clik148_inhibitor/2'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Sandbox_34/Clik148_inhibit_cys25/1'>covalent ligand-bound cysteine protease complex</scene> with Cys25. Five other residues are also involved in the bonding of Clik-148 to papain: Gln19, Gly66, Asp158, Trp177, and Ser205. These participate in hydrophobic, <scene name='Sandbox_34/Clik148ringstacking/2'>aromatic ring-stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>

<scene name='Sandbox_34/Cathepsin_l/1'>Cathepsin L</scene> is an endosomal cysteine protease that is believed to have both physiological and pathophysiological effects on the human body. It has been indicated not only in cancer, rhematoid arthritis, and osteo-arthritis, but its mechanism also appears similar to that of Ebola, SARS, and Leishmania. Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> An interesting inhibitor for cathepsin L developed using papain as the model protease is that of <scene name='Sandbox_34/Clik148_inhibitor/2'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Sandbox_34/Clik148_inhibit_cys25/1'>covalent ligand-bound cysteine protease complex</scene> with Cys25. Five other residues are also involved in the bonding of Clik-148 to papain: Gln19, Gly66, Asp158, Trp177, and Ser205. These participate in hydrophobic, <scene name='Sandbox_34/Clik148ringstacking/2'>aromatic ring-stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>

===Cathepsin K===

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@@ Line 16: / Line 16: @@
 == Structure ==
 <Structure load='9pap' size='390' frame='true' align='left' caption='Papain and Structure' scene='Sandbox_34/Subunitsrandl/3'/>
-Papain is a relatively simple enzyme. It consists of only one chain of 212 residues with three disulfide bonds, illustrated in yellow. The single chain is separated into <scene name='Sandbox_34/Subunitsrandl/1'>two domains</scene>: R is shown in purple, and L in gray. A cleft is formed in which the <scene name='Sandbox_34/2subuwithactivesite/4'>active site</scene>, consisting of cysteine-25, histidine-159, and asparagine-175, resides.<ref name="PDBSum" /> A <scene name='Sandbox_34/Rainbown-c/1'>Rainbow-C</scene> illustration of this shows, from the N-terminus in blue to the C-terminus in red, an easy means by which to track the residues through the molecule. Many hydrogen bonds exist throughout the molecule, holding it in its 3D conformation. These stabilizing bonds, represented in white, are present both in the <scene name='Sandbox_34/Pap_with_h-bonding_btwnbckbne/2'>backbone</scene>, and between <scene name='Sandbox_34/Pap_with_h-bonding_btwnsdchns/3'>residues</scene>.
+Papain is a relatively simple enzyme. It consists of only one chain of 212 residues, with a secondary structure composed of 21%
+<scene name='Sandbox_34/Betasheets/1'>beta sheets</scene> and 25% <scene name='Sandbox_34/Alphahelices/1'>alpha helices</scene>.<ref name="RSCB PDB">http://www.rcsb.org/pdb/explore/explore.do?structureId=9PAP</ref> It's tertiary structure has three disulfide bonds, illustrated in yellow, between Cys22 and Cys63, Cys56, and Cys 95,and Cys153 and Cys200. The single chain is separated into <scene name='Sandbox_34/Subunitsrandl/1'>two domains</scene>: R is shown in purple, and L in gray. A cleft is formed in which the <scene name='Sandbox_34/2subuwithactivesite/4'>active site</scene>, consisting of cysteine-25, histidine-159, and asparagine-175, resides.<ref name="PDBSum" /> A <scene name='Sandbox_34/Rainbown-c/1'>Rainbow-C</scene> illustration of this shows, from the N-terminus in blue to the C-terminus in red, an easy means by which to track the residues through the molecule. Many hydrogen bonds exist throughout the molecule, holding it in its 3D conformation. These stabilizing bonds, represented in white, are present both in the <scene name='Sandbox_34/Pap_with_h-bonding_btwnbckbne/2'>backbone</scene>, and between <scene name='Sandbox_34/Pap_with_h-bonding_btwnsdchns/3'>residues</scene>.
 <scene name='Sandbox_34/Salt_bridges/5'>Salt bridges</scene> also strongly contribute to the stability of the protein structure. In this particular image, clarification of residue coordination is demonstrated by color: paired residues are shown in the same color, oxygen is shown in red, and nitrogen is shown in blue A modified cysteine residue with a sulfhydryl group, <scene name='Sandbox_34/9pap_sulfhydryl_group/1'>cysteine sulfonic acid</scene>, is necessary for the activity of the enzyme<ref>http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/analytical-enzymes/papain.html</ref> In 9PAP, the primary representation of papain used in this article, the sulfhydryl group has been oxidized.  Papain contains many <scene name='Sandbox_34/Hydrophobicpolar/1'>hydrophobic and polar regions</scene>. The <scene name='Sandbox_34/Hydrophobic_residues/1'>hydrophobic residues</scene> are illustrated in gray, and the <scene name='Sandbox_34/Polar_residues/1'>polar residues</scene> are illustrated in magenta.
 In a paper entitled, ''The Structure of Papain Refined at 1.65 A Resoltion'', Kamphuis et al. discovered interesting information on <scene name='Sandbox_34/All_bonding_shenanigans/1'>direct protein-protein contacts</scene> between molecules of papain in solution. These contacts, communicated in Table 7 of their paper, consist of nine hydrogen-bond connections and three ionic interactions. The strongest salt bridge exists between <scene name='Sandbox_34/Arg191asp140intraxn/2'>asparagine-140 and arginine-191</scene>.<ref name="Structure" />
@@ Line 36: / Line 37: @@
 <Structure load='9pap' size='350' frame='true' align='left' caption='Papain and Inhibition' scene='Sandbox_34/9pap_active_site/1' />
 ===Cathepsin L===
-Cathepsin L is an endosomal cysteine protease that is believed to have both physiological and pathophysiological effects on the human body. It has been indicated not only in cancer, rhematoid arthritis, and osteo-arthritis, but its mechanism also appears similar to that of Ebola, SARS, and Leishmania. Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> An interesting inhibitor for cathepsin L developed using papain as the model protease is that of <scene name='Sandbox_34/Clik148_inhibitor/2'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Sandbox_34/Clik148_inhibit_cys25/1'>covalent ligand-bound cysteine protease complex</scene> with Cys25. Five other residues are also involved in the bonding of Clik-148 to papain: Gln19, Gly66, Asp158, Trp177, and Ser205. These participate in hydrophobic, <scene name='Sandbox_34/Clik148ringstacking/2'>aromatic ring-stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>
+<scene name='Sandbox_34/Cathepsin_l/1'>Cathepsin L</scene> is an endosomal cysteine protease that is believed to have both physiological and pathophysiological effects on the human body. It has been indicated not only in cancer, rhematoid arthritis, and osteo-arthritis, but its mechanism also appears similar to that of Ebola, SARS, and Leishmania. Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> An interesting inhibitor for cathepsin L developed using papain as the model protease is that of <scene name='Sandbox_34/Clik148_inhibitor/2'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Sandbox_34/Clik148_inhibit_cys25/1'>covalent ligand-bound cysteine protease complex</scene> with Cys25. Five other residues are also involved in the bonding of Clik-148 to papain: Gln19, Gly66, Asp158, Trp177, and Ser205. These participate in hydrophobic, <scene name='Sandbox_34/Clik148ringstacking/2'>aromatic ring-stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>
 ===Cathepsin K===