User:Cody Couperus/Sandbox 1: Difference between revisions

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==Introduction==

<scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its zymogen, prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor FVa in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:

<scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its [http://en.wikipedia.org/wiki/Zymogen zymogen], prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor [http://en.wikipedia.org/wiki/Factor_V FVa] in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:

* Activating platelets through their protease activated receptors (PARs)<ref name="one"/>

* Activating platelets through their [http://en.wikipedia.org/wiki/Protease-activated_receptor protease activated receptors (PARs)]<ref name="one"/>

* Preventing VWF processing by cleaving ADAMTS13 <ref name="two">PMID: 15388580</ref><ref name="three">PMID: 15994286</ref>

* Preventing [http://en.wikipedia.org/wiki/Von_Willebrand_factor Von Willebrand factor (VWF)] processing by cleaving [http://en.wikipedia.org/wiki/ADAMTS13 ADAMTS13] <ref name="two">PMID: 15388580</ref><ref name="three">PMID: 15994286</ref>

* Enhancing its own production through [[FIX]] activation <ref name="three"/>

* Activating the fibrin crosslinking transglutaminase [[Factor_XIII | FXIII]] <ref>PMID: 4811064</ref>

* Activation of thrombin activatable fibrinolysis inhibitor (TAFI) <ref>PMID: 20229688</ref>

* Activation of [http://www.ncbi.nlm.nih.gov/pubmed/17008302 thrombin activatable fibrinolysis inhibitor (TAFI)] <ref>PMID: 20229688</ref>

Activity of thrombin is regulated physiologically by the serpin inhibitors:

* [[Antithrombin]] <ref name="three"/><ref name='four'>PMID: 24477356</ref><ref name='five'>PMID: 23809129</ref>

* Heparin cofactor II <ref name="three"/><ref name='four'/><ref name='five'/>

* [http://en.wikipedia.org/wiki/Heparin_cofactor_II Heparin cofactor II]<ref name="three"/><ref name='four'/><ref name='five'/>

* Protein C inhibitor <ref name="three"/><ref name='four'/><ref name='five'/>

* [http://en.wikipedia.org/wiki/Protein_C_inhibitor Protein C inhibitor]<ref name="three"/><ref name='four'/><ref name='five'/>

* Protease nexin 1 <ref name="three"/><ref name='four'/><ref name='five'/>

* [http://www.sciencedirect.com/science/article/pii/0968000484900744 Protease nexin 1]<ref name="three"/><ref name='four'/><ref name='five'/>

Generation of thrombin is decreased when thrombin reaches endothelial lining and interacts with [[1fge |thrombomodulin]] which significantly increases activity of thrombin in activating protein C (APC).<ref>PMID: 3029867</ref> This enzyme will go on to inactivate FVa<ref>PMID: 7989361</ref><ref name='six'>PMID: 8639840</ref> and [[Factor_VIII | FVIIIa]]<ref name='six'/> , cofactors for activation of prothrombin<ref>PMID: 15147718</ref> and [[Factor_Xa | FXa]]<ref>PMID: 10881749</ref>, respectively.

Generation of thrombin is decreased when thrombin reaches endothelial lining and interacts with [[1fge |thrombomodulin]] which significantly increases activity of thrombin in activating [http://en.wikipedia.org/wiki/Protein_C protein C (APC)].<ref>PMID: 3029867</ref> This enzyme will go on to inactivate FVa<ref>PMID: 7989361</ref><ref name='six'>PMID: 8639840</ref> and [[Factor_VIII | FVIIIa]]<ref name='six'/> , cofactors for activation of prothrombin<ref>PMID: 15147718</ref> and [[Factor_Xa | FXa]]<ref>PMID: 10881749</ref>, respectively.

By balancing substrate specificity, activity, and inhibition thrombin plays a central role in the blood coagulation cascade. <ref name="three"/>

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[[Image:Electrostatic labeled.png|300px|right|thumb| Thrombin (1PPB) overlayed with electrostatic surface. Structural features 60-loop, γ-loop, exosite I, and exosite II labeled]]

Thrombin is a α/β heterodimer composed of a 36 amino acid A chain and 259 amino acid B chain connected by a <scene name='58/583418/Disulfides_nospin/1'>disufide</scene> bridge between Cys1 and Cys122, in addition to 3 other intrachain disulfide bonds.<ref>PMID: 2583108</ref> Its overall fold is similar to trypsin and chymotrypsin and it belongs to the peptidase S1 protease family<ref>PMID: 18768474</ref>. It is an overall spherical protein with approximate dimensions of 45 X 45 X 50 Å^3.<ref~~>PMID: 2583108<~~/~~ref~~>

Thrombin is a α/β heterodimer composed of a 36 amino acid A chain and 259 amino acid B chain connected by a <scene name='58/583418/Disulfides_nospin/1'>disufide</scene> bridge between Cys1 and Cys122, in addition to 3 other intrachain disulfide bonds.<ref name='eight'>PMID: 2583108</ref> Its overall fold is similar to trypsin and chymotrypsin and it belongs to the peptidase S1 protease family<ref>PMID: 18768474</ref>. It is an overall spherical protein with approximate dimensions of 45 X 45 X 50 Å^3.<ref name='eight'/>

Important structural features include:

* A prominent active site cleft flanked by the 60- and γ-loops

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* Two surface patches referred to as exosite I and exosite II.

The <scene name='58/583418/A_chain_nospin/1' target='0'>A chain</scene> is mostly helical and is wound around the B chain and shaped like a boomerang. It is bound to the B chain mostly through side chain interactions including a salt bridge and H-bond cluster at residues D14, E8, and E14c.<ref~~>PMID: 2583108<~~/~~ref~~> Furthermore the C-terminus region forms a short amphipathic helix with hydrophobic side chains interacting with the B chain.<ref~~>PMID: 2583108<~~/~~ref~~>

The <scene name='58/583418/A_chain_nospin/1' target='0'>A chain</scene> is mostly helical and is wound around the B chain and shaped like a boomerang. It is bound to the B chain mostly through side chain interactions including a salt bridge and H-bond cluster at residues D14, E8, and E14c.<ref name='eight'/> Furthermore the C-terminus region forms a short amphipathic helix with hydrophobic side chains interacting with the B chain.<ref name='eight'/>

The <scene name='58/583418/B_chain/1' target='0'>B chain</scene> contains the active site of the protein and has numerous notable structural features. The active site is formed at the rims of two interacting 6 stranded <scene name='58/583418/Beta_barrel/2'>beta barrel domains</scene>(N-terminal barrel in red and C-terminal barrel in orange) which are surrounded by 4 helical regions and many turns.

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 <StructureSection load='1PPB' size='350' side='right' caption='Thrombin (1PPB) viewed in cartoon representation colored by secondary structure. Active site residues Ser195, Asp102, and His57 are viewed in ball and stick form.' scene='58/583418/Thombin_main_secondary/2'>
 ==Introduction==
-<scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its zymogen, prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor FVa in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:
+<scene name='58/583418/Thombin_main_secondary/2'>Thrombin</scene> is the serine protease that catalyzes the penultimate step in blood coagulation. It is activated from its [http://en.wikipedia.org/wiki/Zymogen zymogen], prothrombin, at the site of tissue injury by [[Factor_Xa | FXa]] and its cofactor [http://en.wikipedia.org/wiki/Factor_V FVa] in the presence of phospholipid membrane and calcium. Thrombin is then able to catalyze the cleavage of [[Fibrinogen | fibrinogen]] to insoluable fibrin which spontaneously polymerizes to form a stable clot.<ref name="zero">PMID: 7023326</ref><ref name="one">PMID: 11001069</ref> Thrombin also acts as a procoagulant by:
-* Activating platelets through their protease activated receptors (PARs)<ref name="one"/>
+* Activating platelets through their [http://en.wikipedia.org/wiki/Protease-activated_receptor protease activated receptors (PARs)]<ref name="one"/>
-* Preventing VWF processing by cleaving ADAMTS13 <ref name="two">PMID: 15388580</ref><ref name="three">PMID: 15994286</ref>
+* Preventing [http://en.wikipedia.org/wiki/Von_Willebrand_factor Von Willebrand factor (VWF)] processing by cleaving [http://en.wikipedia.org/wiki/ADAMTS13 ADAMTS13] <ref name="two">PMID: 15388580</ref><ref name="three">PMID: 15994286</ref>
 * Enhancing its own production through [[FIX]] activation  <ref name="three"/>
 * Activating the fibrin crosslinking transglutaminase [[Factor_XIII | FXIII]] <ref>PMID: 4811064</ref>
-* Activation of thrombin activatable fibrinolysis inhibitor (TAFI) <ref>PMID: 20229688</ref>
+* Activation of [http://www.ncbi.nlm.nih.gov/pubmed/17008302 thrombin activatable fibrinolysis inhibitor (TAFI)] <ref>PMID: 20229688</ref>
 Activity of thrombin is regulated physiologically by the serpin inhibitors:
 * [[Antithrombin]] <ref name="three"/><ref name='four'>PMID: 24477356</ref><ref name='five'>PMID: 23809129</ref>
-* Heparin cofactor II <ref name="three"/><ref name='four'/><ref name='five'/>
+* [http://en.wikipedia.org/wiki/Heparin_cofactor_II Heparin cofactor II]<ref name="three"/><ref name='four'/><ref name='five'/>
-* Protein C inhibitor <ref name="three"/><ref name='four'/><ref name='five'/>
+* [http://en.wikipedia.org/wiki/Protein_C_inhibitor Protein C inhibitor]<ref name="three"/><ref name='four'/><ref name='five'/>
-* Protease nexin 1 <ref name="three"/><ref name='four'/><ref name='five'/>
+* [http://www.sciencedirect.com/science/article/pii/0968000484900744 Protease nexin 1]<ref name="three"/><ref name='four'/><ref name='five'/>
-Generation of thrombin is decreased when thrombin reaches endothelial lining and interacts with [[1fge |thrombomodulin]] which significantly increases activity of thrombin in activating protein C (APC).<ref>PMID: 3029867</ref> This enzyme will go on to inactivate FVa<ref>PMID: 7989361</ref><ref name='six'>PMID: 8639840</ref> and [[Factor_VIII | FVIIIa]]<ref name='six'/> , cofactors for activation of prothrombin<ref>PMID: 15147718</ref> and [[Factor_Xa | FXa]]<ref>PMID: 10881749</ref>, respectively.
+Generation of thrombin is decreased when thrombin reaches endothelial lining and interacts with [[1fge |thrombomodulin]] which significantly increases activity of thrombin in activating [http://en.wikipedia.org/wiki/Protein_C protein C (APC)].<ref>PMID: 3029867</ref> This enzyme will go on to inactivate FVa<ref>PMID: 7989361</ref><ref name='six'>PMID: 8639840</ref> and [[Factor_VIII | FVIIIa]]<ref name='six'/> , cofactors for activation of prothrombin<ref>PMID: 15147718</ref> and [[Factor_Xa | FXa]]<ref>PMID: 10881749</ref>, respectively.
 By balancing substrate specificity, activity, and inhibition thrombin plays a central role in the blood coagulation cascade. <ref name="three"/>
@@ Line 48: / Line 48: @@
 [[Image:Electrostatic labeled.png|300px|right|thumb| Thrombin (1PPB) overlayed with electrostatic surface. Structural features 60-loop, γ-loop, exosite I, and exosite II labeled]]
-Thrombin is a α/β heterodimer composed of a 36 amino acid A chain and 259 amino acid B chain connected by a <scene name='58/583418/Disulfides_nospin/1'>disufide</scene> bridge between Cys1 and Cys122, in addition to 3 other intrachain disulfide bonds.<ref>PMID: 2583108</ref> Its overall fold is similar to trypsin and chymotrypsin and it belongs to the peptidase S1 protease family<ref>PMID: 18768474</ref>. It is an overall spherical protein with approximate dimensions of 45 X 45 X 50 Å^3.<ref>PMID: 2583108</ref>
+Thrombin is a α/β heterodimer composed of a 36 amino acid A chain and 259 amino acid B chain connected by a <scene name='58/583418/Disulfides_nospin/1'>disufide</scene> bridge between Cys1 and Cys122, in addition to 3 other intrachain disulfide bonds.<ref name='eight'>PMID: 2583108</ref> Its overall fold is similar to trypsin and chymotrypsin and it belongs to the peptidase S1 protease family<ref>PMID: 18768474</ref>. It is an overall spherical protein with approximate dimensions of 45 X 45 X 50 Å^3.<ref name='eight'/>
 Important structural features include:
 * A prominent active site cleft flanked by the 60- and γ-loops
@@ Line 54: / Line 54: @@
 * Two surface patches referred to as exosite I and exosite II.
-The <scene name='58/583418/A_chain_nospin/1' target='0'>A chain</scene> is mostly helical and is wound around the B chain and shaped like a boomerang. It is bound to the B chain mostly through side chain interactions including a salt bridge and H-bond cluster at residues D14, E8, and E14c.<ref>PMID: 2583108</ref> Furthermore the C-terminus region forms a short amphipathic helix with hydrophobic side chains interacting with the B chain.<ref>PMID: 2583108</ref>
+The <scene name='58/583418/A_chain_nospin/1' target='0'>A chain</scene> is mostly helical and is wound around the B chain and shaped like a boomerang. It is bound to the B chain mostly through side chain interactions including a salt bridge and H-bond cluster at residues D14, E8, and E14c.<ref name='eight'/> Furthermore the C-terminus region forms a short amphipathic helix with hydrophobic side chains interacting with the B chain.<ref name='eight'/>
 The <scene name='58/583418/B_chain/1' target='0'>B chain</scene> contains the active site of the protein and has numerous notable structural features. The active site is formed at the rims of two interacting 6 stranded <scene name='58/583418/Beta_barrel/2'>beta barrel domains</scene>(N-terminal barrel in red and C-terminal barrel in orange) which are surrounded by 4 helical regions and many turns.