Enrico Di Cera, M.D., professor of biochemistry and molecular biophysics, has received a $1.4 million grant from the National Heart, Lung, and Blood Institute. Di Cera is studying the blood-clotting protein thrombin.
He discovered that sodium ions enhance thrombin's performance by prompting it to change shape. This shape change enables thrombin to interact more efficiently with other proteins involved in clotting.
By altering thrombin at specific sites, the researchers will map the region responsible for the shape change. They also will investigate the molecular events that allow this region to communicate with other parts of the molecule.
A second project will locate the binding sites for various proteins on both the sodium-free and sodium-bound forms of thrombin. This work should reveal whether different sites account for thrombin's various functions. If so, it might be possible to develop drugs that block one site and not others.
Using X-ray crystallography, the researchers also will determine the detailed 3-D structures of both forms of thrombin and determine how altering the protein at specific sites affects structure.
Finally, they will introduce a sodium-binding site into the corresponding region of tissue plasminogen activator (tPA), which does not normally bind sodium. Used to dissolve clots in heart-attack and stroke patients, tPA might work faster with a sodium-binding site.
Thrombin and tPA are members of a large family of protein-cutting enzymes called serine proteases. Therefore, Di Cera's research should generate rational strategies for enhancing numerous enzymes used in medicine and biotechnology.
