User:Cody Couperus/Sandbox 1

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* Enhancing its own production through [[FIX]] activation <ref>PMID: 15994286</ref>
* Enhancing its own production through [[FIX]] activation <ref>PMID: 15994286</ref>
* Activating the fibrin crosslinking transglutaminase [[Factor_XIII | FXIII]] <ref>PMID: 4811064</ref>
* Activating the fibrin crosslinking transglutaminase [[Factor_XIII | FXIII]] <ref>PMID: 4811064</ref>
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* Activation of thrombin activatable fibrinolysis inhibitor (TAFI) <ref>PMID: 20229688</re>
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* Activation of thrombin activatable fibrinolysis inhibitor (TAFI) <ref>PMID: 20229688</ref>
Activity of thrombin is regulated physiologically by the serpin inhibitors:
Activity of thrombin is regulated physiologically by the serpin inhibitors:
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Prothrombin is the zymogen form of thrombin. From N-terminal to C-terminal it consists of a Gla domain, two kringle domains, and a catalytic domain.
Prothrombin is the zymogen form of thrombin. From N-terminal to C-terminal it consists of a Gla domain, two kringle domains, and a catalytic domain.
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Prothrombin is activated by prothrombinase which consists of FXa, FVa, calcium, and a phospholipid surface. In vivo the first cleavage occurs at the R320-I321 bond, corresponding to residues 15-16 in thrombin which is the N-terminus of the B chain, producing meizothrombin. Subsequent cleavage at R271-T272 yields thrombin. The initial cleavage can also occur at R271 resulting in prothrombin-2 which will then be cleaved at R320 to produce thrombin.
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Prothrombin is activated by prothrombinase which consists of FXa, FVa, calcium, and a phospholipid surface. In vivo the first cleavage occurs at the R320-I321 bond, corresponding to residues 15-16 in thrombin which is the N-terminus of the B chain, producing meizothrombin.<ref>PMID: 22944689</ref> Subsequent cleavage at R271-T272 yields thrombin.<ref>PMID: 22944689</ref> The initial cleavage can also occur at R271 resulting in prothrombin-2 which will then be cleaved at R320 to produce thrombin.<ref>PMID: 1995649</ref>
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After cleavage by prothrombinase the new B chain N-terminus (Ile16) folds into the core protease domain and forms a salt bridge with Asp194. This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the correct conformation for the S1 pocket and oxanion hole for catalysis.
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After cleavage by prothrombinase the new B chain N-terminus (Ile16) folds into the core protease domain and forms a salt bridge with Asp194.<ref>PMID: 22944689</ref> This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the correct conformation for the S1 pocket and oxanion hole for catalysis.<ref>PMID: 22944689</ref>
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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]]
[[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]]
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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. Its overall fold is similar to trypsin and chymotrypsin and it belongs to the peptidase S1 protease family. It is an overall spherical protein with approximate dimensions of 45 X 45 X 50 Å^3.<ref>PMID: 2583108</ref>
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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>
Important structural features include:
Important structural features include:
* A prominent active site cleft flanked by the 60- and γ-loops
* 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.
* Two surface patches referred to as exosite I and exosite II.
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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. Furthermore the C-terminus region forms a short amphipathic helix with hydrophobic side chains interacting with the B chain.
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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/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/1'>beta barrel domains</scene> which are surrounded by 4 helical regions and many turns.
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/1'>beta barrel domains</scene> which are surrounded by 4 helical regions and many turns.

Revision as of 13:15, 28 April 2014

Thrombin: Structure and Function

Thrombin (1PPB) viewed in cartoon representation colored by secondary structure. Active site residues Ser195, Asp102, and His57 are viewed in ball and stick form.

Drag the structure with the mouse to rotate

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Cody Couperus

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