3D structure of TBKI opens new avenue for a targeted fight against diseases linked to inflammation
Uncontrolled inflammation has been linked to the onset of many diseases, from rheumatoid arthritis to certain cancers. One of the key enzymes in triggering inflammation, the Tank-binding kinase I (TBKI), is attracting an increasing attention as a potential drug-target in the fight against several diseases. Researchers at EMBL Grenoble have published the high-resolution 3D structure of this enzyme, both in its active and its inactive forms, in Cell Reports. This finding could have widespread consequences for the design of new drug-candidates.
Until now, researchers only knew the structure of the active sites of TBKI. Thanks to this detailed X-ray analysis, they now have a clear and more precise image of the enzyme as a whole: it is made of two symmetrical parts, each containing 3 subunits. By comparing the active and inactive structures of TBKI, researchers were able to determine that most of the enzyme’s structure remains the same upon activation, except for an active kinase site that changes conformation.
“It is very important to know the exact structure of TBKI both in its active and in its inactive forms,” explains Daniel Panne, from EMBL Grenoble, who led the study. “All kinases look similar in their active forms but not in their inactive forms, so knowing the latter is important in order to design more targeted drug-candidates.”
TBKI has been linked to many diseases linked to inflammation, such as obesity-related metabolic diseases, rheumatoid arthritis, or certain cancers. Knowing the details of its structure with high precision will enable researchers to design targeted drug-candidates that should specifically disrupt this one enzyme and, further down a long road, become innovative treatments for many diseases.
Crystal Structure and Mechanism of Activation of TANK-Binding Kinase 1 - Amede Larabi, Juliette M. Devos, Sze-Ling Ng, Max H. Nanao, Adam Round, Tom Maniatis, and Daniel Panne – Published online in Cell Reports on 28 February 2013