Papain: Difference between revisions

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<scene name='Papain/Cathepsin_l/1'>Cathepsin L</scene>, another inhibitor of Papain, 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 and osteo arthritis, and Alzheimer's, but its mechanism also appears similar to that of Ebola, SARS, Leishmania, malaria, Chagas' disease, African trypanosomiasis, toxoplasmosis, and amoebiasis.<ref> PMID:20920298 </ref> Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> Cathepsin L interacts with the <scene name='Papain/Cathepsin_l_interaction_w_pap/2'>residues</scene> Gln-19, Cys-25, Gly-66, Asp-158, and Trp-177 by hydrogen bonding them (Cathepsin L is illustrated in CPK coloring while the interacting sites of Papain are also shown in CPK). In addition to hydrogen bonding, hydrophobic interactions exist to exclude water, allowing the papain enzyme and Cathepsin L to associate even closer.

An interesting inhibitor for Cathepsin L developed using papain as the model protease is that of <scene name='Papain/Ke_clik148_inhibitor/4'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Papain/Ke_clik148_inhibit_cys25/2'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other <scene name='Papain/Ke_clik148_inhibit_cys25/3'>residues</scene> are also involved in the bonding of Clik-148 to papain: Gln-19, Gly-66, Asp-158, Trp-177, and Ser-205. These participate in hydrophobic, <scene name='Papain/Keclik148ringstacking/2'>aromatic ring stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>

An interesting inhibitor for Cathepsin L developed using papain as the model protease is that of <scene name='Papain/Ke_clik148_inhibitor/4'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Papain/Ke_clik148_inhibit_cys25/2'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other <scene name='Papain/Ke_clik148_inhibit_cys25/3'>residues</scene>, labeled in white, are also involved in the bonding of Clik-148 to papain: Gln-19, Gly-66, Asp-158, Trp-177, and Ser-205. These participate in hydrophobic, <scene name='Papain/Keclik148ringstacking/2'>aromatic ring stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>

==='''Stefin B'''===

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<scene name='Papain/Sk_inhibitor_0/2'>Stefin B</scene> acts as a competitive inhibitor to cysteine proteases-- it binds tightly but reversibly to the papain active site. Stefin inhibitors are characterized by M<sub>r</sub> of about 11,000, no disulfide bonds and no associated carbohydrates.

In Stefin B, the ~~Gly9~~ residue along with <scene name='Papain/Sk_inhibitor_6/3'>two hairpin loops</scene> form a "wedge" complementary to the active site groove of papain. This wedge makes extensive and tight interactions with papain and a total of 128 intermolecular atom-atom interactions occur. <scene name='Papain/Sk_inhibitor_1/1'>Residue segments</scene> Met6-Pro11, Gln53-Asn59, Gln101-His104 and ~~Tyr124~~-~~Phe125~~ on the wedge all have some interaction to the enzyme though not always direct. All residues from the base and both sides of the <scene name='Papain/Sk_inhibitor_2/1'>active site cleft</scene> are involved in the complex with the inhibtor (~~Trp177~~, ~~Ser21~~, ~~Cys63~~, ~~Cys25~~, ~~Asp158~~ and ~~His159~~).

In Stefin B, the Gly-9 residue along with <scene name='Papain/Sk_inhibitor_6/3'>two hairpin loops</scene> form a "wedge" complementary to the active site groove of papain. This wedge makes extensive and tight interactions with papain and a total of 128 intermolecular atom-atom interactions occur. <scene name='Papain/Sk_inhibitor_1/1'>Residue segments</scene> Met6-Pro11, Gln53-Asn59, Gln101-His104 and Tyr-124 - Phe-125 on the wedge all have some interaction to the enzyme though not always direct. All residues from the base and both sides of the <scene name='Papain/Sk_inhibitor_2/1'>active site cleft</scene> are involved in the complex with the inhibtor (Trp-177, Ser-21, Cys-63, Cys-25, Asp-158 and His-159).

There are a small number of <scene name='Papain/Sk_inhibitor_3/1'>direct hydrogen bonds</scene> between stefin B and papain, however there are many more polar interactions mediated by <scene name='Papain/Sk_inhibitor_4/3'>solvent bridges</scene>. Thirteen solvent molecules bridge polar residues of the enzyme and inhibitor. Seventeen hydrogen bonds are made with a solvent molecule and stefin. Fourteen of these bridges form a papain contact. The rest of the interactions are largely hydrophobic-- involving apolar <scene name='Papain/Sk_inhibitor_5/3'>Van der Waals interactions</scene>. <ref> PMID:2347312 </ref>

There are a small number of <scene name='Papain/Sk_inhibitor_3/1'>direct hydrogen bonds</scene> between stefin B and papain, however there are many more polar interactions mediated by <scene name='Papain/Sk_inhibitor_4/3'>solvent bridges</scene>. Thirteen solvent molecules bridge polar residues of the enzyme and inhibitor. Seventeen hydrogen bonds are made with a solvent molecule and stefin. Fourteen of these bridges form a papain contact. The rest of the interactions are largely hydrophobic-- involving apolar <scene name='Papain/Sk_inhibitor_5/3'>Van der Waals interactions</scene>.<ref> PMID:2347312 </ref>

</StructureSection>

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@@ Line 49: / Line 49: @@
 <scene name='Papain/Cathepsin_l/1'>Cathepsin L</scene>, another inhibitor of Papain, 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  and osteo arthritis, and Alzheimer's, but its mechanism also appears similar to that of Ebola, SARS, Leishmania, malaria, Chagas' disease, African trypanosomiasis, toxoplasmosis, and amoebiasis.<ref> PMID:20920298 </ref>  Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> Cathepsin L interacts with the <scene name='Papain/Cathepsin_l_interaction_w_pap/2'>residues</scene> Gln-19, Cys-25, Gly-66, Asp-158, and Trp-177 by hydrogen bonding them (Cathepsin L is illustrated in CPK coloring while the interacting sites of Papain are also shown in CPK). In addition to hydrogen bonding, hydrophobic interactions exist to exclude water, allowing the papain enzyme and Cathepsin L to associate even closer.
-An interesting inhibitor for Cathepsin L developed using papain as the model protease is that of <scene name='Papain/Ke_clik148_inhibitor/4'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Papain/Ke_clik148_inhibit_cys25/2'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other <scene name='Papain/Ke_clik148_inhibit_cys25/3'>residues</scene> are also involved in the bonding of Clik-148 to papain: Gln-19, Gly-66, Asp-158, Trp-177, and Ser-205. These participate in hydrophobic, <scene name='Papain/Keclik148ringstacking/2'>aromatic ring stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>
+An interesting inhibitor for Cathepsin L developed using papain as the model protease is that of <scene name='Papain/Ke_clik148_inhibitor/4'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Papain/Ke_clik148_inhibit_cys25/2'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other <scene name='Papain/Ke_clik148_inhibit_cys25/3'>residues</scene>, labeled in white, are also involved in the bonding of Clik-148 to papain: Gln-19, Gly-66, Asp-158, Trp-177, and Ser-205. These participate in hydrophobic, <scene name='Papain/Keclik148ringstacking/2'>aromatic ring stacking</scene>, and hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>
 ==='''Stefin B'''===
@@ Line 55: / Line 55: @@
 <scene name='Papain/Sk_inhibitor_0/2'>Stefin B</scene> acts as a competitive inhibitor to cysteine proteases-- it binds tightly but reversibly to the papain active site.  Stefin inhibitors are characterized by M<sub>r</sub> of about 11,000, no disulfide bonds and no associated carbohydrates.
-In Stefin B, the Gly9 residue along with <scene name='Papain/Sk_inhibitor_6/3'>two hairpin loops</scene> form a "wedge" complementary to the active site groove of papain.  This wedge makes extensive and tight interactions with papain and a total of 128 intermolecular atom-atom interactions occur.  <scene name='Papain/Sk_inhibitor_1/1'>Residue segments</scene> Met6-Pro11, Gln53-Asn59, Gln101-His104 and Tyr124-Phe125 on the wedge all have some interaction to the enzyme though not always direct.  All residues from the base and both sides of the <scene name='Papain/Sk_inhibitor_2/1'>active site cleft</scene> are involved in the complex with the inhibtor (Trp177, Ser21, Cys63, Cys25, Asp158 and His159).
+In Stefin B, the Gly-9 residue along with <scene name='Papain/Sk_inhibitor_6/3'>two hairpin loops</scene> form a "wedge" complementary to the active site groove of papain.  This wedge makes extensive and tight interactions with papain and a total of 128 intermolecular atom-atom interactions occur.  <scene name='Papain/Sk_inhibitor_1/1'>Residue segments</scene> Met6-Pro11, Gln53-Asn59, Gln101-His104 and Tyr-124 - Phe-125 on the wedge all have some interaction to the enzyme though not always direct.  All residues from the base and both sides of the <scene name='Papain/Sk_inhibitor_2/1'>active site cleft</scene> are involved in the complex with the inhibtor (Trp-177, Ser-21, Cys-63, Cys-25, Asp-158 and His-159).
-There are a small number of <scene name='Papain/Sk_inhibitor_3/1'>direct hydrogen bonds</scene> between stefin B and papain, however there are many more polar interactions mediated by <scene name='Papain/Sk_inhibitor_4/3'>solvent bridges</scene>.  Thirteen solvent molecules bridge polar residues of the enzyme and inhibitor.  Seventeen hydrogen bonds are made with a solvent molecule and stefin.  Fourteen of these bridges form a papain contact.  The rest of the interactions are largely hydrophobic-- involving apolar <scene name='Papain/Sk_inhibitor_5/3'>Van der Waals interactions</scene>. <ref> PMID:2347312 </ref>
+There are a small number of <scene name='Papain/Sk_inhibitor_3/1'>direct hydrogen bonds</scene> between stefin B and papain, however there are many more polar interactions mediated by <scene name='Papain/Sk_inhibitor_4/3'>solvent bridges</scene>.  Thirteen solvent molecules bridge polar residues of the enzyme and inhibitor.  Seventeen hydrogen bonds are made with a solvent molecule and stefin.  Fourteen of these bridges form a papain contact.  The rest of the interactions are largely hydrophobic-- involving apolar <scene name='Papain/Sk_inhibitor_5/3'>Van der Waals interactions</scene>.<ref> PMID:2347312 </ref>
 </StructureSection>