Great collaborative effort by ESR Antonio Carlesso based in the University of Göteborg, Sweden and ESR Chetan Chintha based in NUI Galway, Ireland and their supervisors Leif Eriksson and Afshin Samali. This work was published in ACS Omega by the American Chemical Society.
Their study “Binding Analysis of the Inositol-Requiring Enzyme 1 Kinase Domain ” analyses the available structural data of the IRE1 kinase domain and provides insights into the design of novel kinase inhibitors.
Inositol-requiring enzyme 1 (IRE1) is an orchestrator of the unfolded protein response (UPR), the cellular response to endoplasmic reticulum (ER) stress that plays a crucial role in tumor development. IRE1 signaling is the most evolutionary conserved branch of the UPR. Under ER stress, the IRE1 luminal domain undergoes a conformational change to multimerize, resulting in transautophosphorylation and activation of the cytosolic kinase and endoribonuclease domain. Adenosine triphosphate-competitive inhibitors that bind to the IRE1 kinase site can modulate the activity of the RNase domain through an allosteric relationship between the IRE1 kinase and RNase domains. This aim of their study was to investigate the available structural data of the IRE1 kinase domain and provide insights into the design of novel kinase inhibitors. To this end, a detailed analysis of IRE1 kinase active site and investigation of suitable structures for virtual screening studies were performed. The results indicate in silico target fishing as an appropriate strategy for the identification of novel IRE1 kinase binders, further validating the robustness of the in silico protocol. Importantly, the study highlights the kinase-inhibiting RNase attenuator (KIRA)-bound protein data bank 4U6R structure as the best protein structure to perform virtual screening to develop diverse and more potent KIRA-like IRE1 kinase inhibitors that are capable of allosterically affecting the RNase activity.
Well done to the ESRs and their supervisors!!