Abstract
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 trans-autophosphorylation 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. The current study aims at the investigation of available structural data of the IRE1 kinase domain and provides 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.
Highlights
The failure of cells to appropriately fold and modify secretory and transmembrane proteins leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER).[1]
Sequence similarity and sequence identity analysis of inositol-requiring protein 1 (IRE1) in different species revealed that the primary sequence of the cytosolic domain of yeast IRE1 has ∼39% sequence identity compared with that of human IRE1, whereas murine IRE1 displays a sequence identity of more than 85% compared to human IRE1 (Figure S1)
Amino-acid residues at a distance of 5.0 Å from the cocrystallized ligands in human IRE1 are highly conserved through the species and are highlighted in Figures S1 and S2
Summary
The failure of cells to appropriately fold and modify secretory and transmembrane proteins leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER).[1] Under these conditions of “ER stress”, the unfolded protein response (UPR) is initiated by the activation of three sensor proteins on the ER membrane: inositol-requiring protein 1 (IRE1), protein kinase R (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6).[2] Among the three branches, the IRE1 pathway is the most evolutionarily conserved and represents the sole branch of the UPR in yeast.[3] This pathway plays a critical role in a variety of physiological and disease conditions, including B cell and adipocyte differentiation, secretory capacity of pancreatic beta cells and salivary organs, neurodegeneration, obesity, and insulin resistance.[2] a detailed understanding of the regulatory mechanisms underlying mammalian IRE1 activation is essential to the development of therapeutics.[4]. IRE1α (hereafter called IRE1) is ubiquitously expressed and plays an important role in how cells and organisms respond to ER stress, whereas IRE1β is expressed primarily in the epithelial cells of the gastrointestinal tract and the lung but is absent in the liver and pancreas and participates in mucosal secretion and lipid transport in the gut.[6]
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