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."