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More about
Dr. Mather:

Dr. Mather's CV in brief

Publications

Cardiovascular Biology Research Program

Timothy Mather, Ph.D. Assistant Member, Cardiovascular Biology Research Program

Research Interests
In blood coagulation, one of the significant challenges is how to regulate the procoagulant response to vascular injury so that the growing clot seals a wound but does not propagate downstream with the flowing of blood. The body responds to this challenge by tasking thrombin, the major clot forming enzyme, with the additional activity of triggering the natural anticoagulant pathway leading to the down regulation of its own production. The key step initiating this negative feedback loop occurs when thrombin binds to its cofactor thrombomodulin on the vessel wall. A growing body of biochemical evidence indicates that the formation of this complex not only blocks thrombin’s clot-forming activities and initiates its anticoagulant function, but that it does so by inducing an allosteric change in thrombin’s active site.

Our laboratory is working to understand how this alteration in thrombin structure leading to a change in its function occurs. By using the techniques of biochemistry, molecular biology and X-ray crystallography, we are determining the three-dimensional molecular structure of a series of forms and complexes of thrombin and thrombomodulin, shedding light on the subtle mechanisms used in performing this critical task. We have identified several structural elements in thrombomodulin which are involved and recently have determined the only structure of thrombin to date with both its active site and thrombomodulin binding site free of either intentional or opportunistic ligands. This structure represents the conformation closest to the native plasma form of thrombin seen thus far and highlights for the first time some of the details of the allosteric conformational changes induced by thrombomodulin binding.

In addition to building on our growing understanding
of how these proteins normally function, we hope to gain insight into the way alterations impacting this elegant system may contri-bute to the development of coagulation defects. Further, we are using our detailed molecular understanding as the basis for structure-based ligand design studies to develop approaches that will aid in restoring balance to the conditions of thrombotic disease.

Joined OMRF Scientific Staff in 1997.

Mailing Address
Oklahoma Medical Research Foundation, MS 14
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-7858
Fax: (405) 271-7510
E-mail: Tim-Mather@omrf.org