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

November 19, 2004

Bethesda, MD - Scientists have determined the crystal structure of a protein kinase C (PKC) isozyme, in this case the novel PKC family member PKC theta (PKCΘ). This structure should prove extremely useful in the rational design of small molecule inhibitors of PKCΘ, 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.

PKCΘ 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.

"PKCΘ 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 PKCΘ 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 PKCΘ 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 PKCΘ for use as potential therapeutics," says Dr. Somers. "Modulation of PKCΘ 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."
-end-
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 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 www.asbmb.org.

American Society for Biochemistry and Molecular Biology

Related Crystal Structure Articles from Brightsurf:

Getting single-crystal diamond ready for electronics
Researchers from Osaka University and collaborating partners polished single-crystal diamond to near-atomic smoothness without damaging it.

Crystal structure of SARS-CoV-2 papain-like protease
The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before.

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites
Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites.

Photonic crystal light converter
Spectroscopy is the use of light to analyze physical objects and biological samples.

Crystal structure discovered almost 200 years ago could hold key to solar cell revolution
Solar energy researchers are shining their scientific spotlight on materials with a crystal structure discovered nearly two centuries ago.

Crystal wars
Scientists at The University of Tokyo and Fudan University researched the process of crystallization in which competing structural forms coexist.

Melting a crystal topologically
Physicists at EPFL have successfully melted a very thin crystal of magnetic quasi-particles controllably, as turning ice into water.

The makings of a crystal flipper
Hokkaido University scientists have fabricated a crystal that autonomously flips back and forth while changing its flipping patterns in response to lighting conditions.

Crystal power
Scientists at the US Department of Energy's Argonne National Laboratory have created and tested a single-crystal electrode that promises to yield pivotal discoveries for advanced batteries under development worldwide.

Pressing 'pause' on nature's crystal symmetry
From snowflakes to quartz, nature's crystalline structures form with a reliable, systemic symmetry.

Read More: Crystal Structure News and Crystal Structure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.