Nature Structural & Molecular Biology pp 857-867

The body's clotting system causes certain blood proteins (called clotting factors) to work together to form a blood clot. Excess blood clots can lead to potentially fatal conditions such as a heart attack or stroke and anticoagulation drugs, such as heparin, are commonly used during surgery or dialysis to prevent their formation in the blood vessel. Two papers in the September issue of Nature Structural & Molecular Biology report the structure of a synthetic heparin molecule bound to two proteins involved in the clotting system. These structures could facilitate the design of improved heparin-like anticoagulation drugs for clinical applications.

Clotting factor Thrombin, a clotting factor produced by the body, plays a pivotal role in the coagulation process. Clotting can be prevented by administering drugs such as heparin, which binds to and activates antithrombin. This protein circulates in the blood and prevents clotting by binding to heparin and thrombin simultaneously. Now, two groups, Gettins and colleagues at the University of Illinois (Chicago) and Huntington and colleagues at the University of Cambridge (Cambridge, UK) have independently determined the crystal structures of a synthetic heparin molecule bound to thrombin and antithrombin. The structures reveal that heparin bridges the two proteins to hold them in close proximity. Furthermore, the structures explain why synthetic heparin molecules must be a certain length to be effective anticoagulation drugs. These observations provide a basis for the antithrombotic properties of therapeutic heparins.