New protein structure may aid in design of therapeutics for autoimmune disease

Main Category: Biology / Biochemistry
Article Date: 20 Nov 2004 - 0:00 PDT

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Scientists have determined the crystal structure of a protein kinase C (PKC) isozyme, in this case the novel PKC family member PKC theta (PKCÈ). This structure should prove extremely useful in the rational design of small molecule inhibitors of PKCÈ, which has been implicated in T-cell mediated disease processes including inflammation and autoimmunity.

The research appears as the "Paper of the Week" in the November 26 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

PKCÈ is a key signaling molecule in a class of immune cells called T lymphocytes, or T cells. These cells recognize short amino acid chains, or antigens, that are displayed on the surface of antigen-presenting cells and initiate immune responses when activated by the antigens.

"PKCÈ is selectively recruited to the contact region between T cells and antigen-presenting cells where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation," explains Dr. Will Somers, of Wyeth Research. "Inhibiting PKCÈ signal transduction results in defects in T cell activation and cytokine production."

Dr. Somers and his colleagues at Wyeth determined the three-dimensional structure of the catalytic domain of PKCÈ using x-ray crystallography. "This is the first structure of a PKC at atomic resolution," notes Dr. Somers. "Moreover, the structure reported here was solved in the presence of the high potency protein kinase inhibitor, staurosporine, revealing the structural basis of inhibitor binding."

Dr. Somers believes his results have the potential to aid in identifying selective inhibitors of kinase function that can act as therapeutics for diseases in which T cells are targeting native rather than foreign antigens. Inhibiting PKC in these cases would disable the T cells and halt the autoimmune reaction. Currently, several PKC inhibitors are being used in clinical trials for various types of cancer and diabetes-related retinopathy.

"This structure provides a starting point for the rational drug design of high potency inhibitors of the catalytic activity of PKCÈ for use as potential therapeutics," says Dr. Somers. "Modulation of PKCÈ kinase activity presents an ideal therapeutic target in T cell mediated disease processes, including T cell leukemias and T cell mediated autoimmune and respiratory diseases such as asthma."

The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at http://www.jbc.org.

The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.

For more information about ASBMB, see the Society's website at http://www.asbmb.org.

Contact: Nicole Kresge
nkresge@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology

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