User:Oluwapeluwa Sangoseni/Sandbox 1

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Overview

Thrombin is one of the many essential molecules that our body produces and uses to consistently maintain homeostasis. It is a serine protease that acts as both a procoagulant and an anticoagulant, and is essential for blood clot formation, among other functions, such as causing inflammation, repairing tissue, and forming new blood vessels (1).As a procoagulant, in order to promote blood clotting, thrombin cleaves fibrinogen, a soluble protein that can be found in blood plasma, to produce fibrin. Fibrin is an insoluble protein that can be used, with the addition of aggregated platelets (which are also activated by thrombin), to form blood clots by creating meshesthat stop the flow of blood. This is important to prevent the loss of too much blood in the event of an injury that ruptures or damages blood vessels. Thrombin can also induce the coagulation pathway to produce more thrombin by activation of factor XI, and cofactors V and VIII (1). As said before, it also acts as a regulatory anticoagulant by binding to thrombomodulin. Thrombomodulin is a receptor glycoprotein found on the surface of the membranes of endothelial cells, and when thrombin binds to it, it activates the protein C pathway to start a process known as fibrinolysis, which breaks down fibrin and destroys blood clots (2). This is required to prevent excessive blood clotting, which would be problematic as required blood flow may be impeded. Thrombin also regulates fibrinolysis by activating carboxypeptidase B2, also known as thrombin activatable fibrinolysis inhibitor. With this wide array of necessary functions, thrombin is a very important enzyme for maintenance of our bodies.

Function and Structure

Thrombin alone does not cleave fibrinogen, however, and the process is far more complex than one would initially be led to believe. Several molecules also participate in the process, including 6P9U. Most research and data for this molecule has only been conducted and compiled very recently, as the protein data was only deposited in the PDB in mid-late 2019, so, compared to other well-known molecules, there is still quite a bit of work that can be done to learn more about it (3). 6P9U is the crystallized structure of the human thrombin mutant, W215A. Data about this molecule’s structure was compiled using X-ray diffraction, at a resolution of 3.3 Å. It is found in humans, and features an 8-carbon chain structure. It has a cyclic C2 symmetry, and is a hetero 4 mer with the stoichiometry equation A2B2, meaning it has 2 alpha sub units, and 2 beta sub units. In terms of its macromolecular content, it has a total structural weight of 141170.61 Daltons, and features an atom count of 9004. It has a residue count of 1216, with two unique protein chains. These two unique chains consist of two different prothrombin or coagulation factor II macromolecules, with different sequence lengths (31 and 273). Both are expressed by the gene F2. The macromolecule also contains two ligands that bind to it: a Zinc ion (Zn2+), and n-acetyl-D-glucosamine (C8H15NO6). 6P9U/W215A serves as a residue for a hydrolase, facilitating hydrolysis for thrombin, in which a molecule of water is used to break bonds between atoms or molecules. This allows for the required peptide bonds to be cleavedto enable the conversion of fibrinogen to fibrin (3). 6P9U/W215A’s functionality and uses extend to a wider variety of possibilities than just cleaving peptide bonds, however.

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Structural highlights

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