User:Yunlong Zhao/Sandbox 1

Introduction

Heparin is a type of glycosaminoglycan chain that is secreted by human mast cell. Heparin exists in many isoforms and is often sulfated at specific sites. Because of the heterogeneity in structure and distribution of negative charge within those sulfate groups, heparin can bind multiple types of proteins and participate in many different biological processes, such as anticoagulation. Therefore polysaccharides, the low molecular weight products that are originated from digested heparin was often used in the therapy of many diseases such as atrial fibrillation and thrombosis.

Heparin is usually localized on the surface of cells and the complex with matrix proteins. This interesting discovery suggests that heparin exists in the form of “immobile phase” attaching antithrombin and activates its function as an anticoagulant factor in the circulation system. In an anticoagulant process, antithrombin needs to bind to some coagulant proteases such as Factor Xa or thrombin and “neutralizes” their activity. There are several hypotheses to explain how the heparin chains activate this process. A simple model is that a long heparin chain could be a scaffold to improve the possibility of antithrombin contacting with other proteins. ^[1] Another direct model is that specific sulfate-containing heparin fragments (oligosaccharides) can allosterically enhance the binding affinity between antithrombin and thrombin or Factor Xa. We are going to describe the structural basis of the second model in the rest of contexts. ^[2]

Structure features and activation of latent antithrombin

Antithrombin is a natural inhibitor of many serine proteases and it contains an exposed inhibitory loop (shown in blue color in figure 1) to intrude the catalytic site of proteases. The peptide bond between R393-S394 (shown as the sphere model in figure 1) plays a critical role in the inhibitory binding. However, the exposure of the inhibitory loop requires a conformational change during activation. In the latent state of antithrombin, this loop is fully buried in the four-strands beta sheet to form a new five-strands beta sheet. This remarkable conformational change of inhibitory loop highlights the activation mechanism of latent antithrombin, illustrated in fugure 1.

Figure 1

The mechanism of heparin regulating antithrombin thrombin interaction

Green scene 1 will be the interface between AT and thrombin Green scene 2 will be the the interface structure plus heparin

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.