7BMK

ATP-Competitive Partial Antagonists-'PAIR's-Rheostatically Modulate IRE1alpha's Kinase Helix-alphaC to Segregate its RNase-Mediated Biological Outputs

Summary for 7BMK

• Entry DOI: 10.2210/pdb7bmk/pdb
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, 2,2,2-tris(fluoranyl)-~{N}-[4-[3-[2-[[(3~{S})-piperidin-3-yl]amino]pyrimidin-4-yl]pyridin-2-yl]oxynaphthalen-1-yl]ethanesulfonamide, GLYCEROL, ... (7 entities in total)
• Functional Keywords: kinase, kinase inhibitor, transferase, transferase inhibitor, unknown function
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 102917.21

Authors

Feldman, H.C.,Ghosh, R.,Auyeung, V.,Mueller, J.L.,Vidadala, V.N.,Olivier, A.,Backes, B.J.,Zikherman, J.,Papa, F.R.,Maly, D.J. (deposition date: 2021-01-20, release date: 2021-09-29, Last modification date: 2024-06-19)

Primary citation

Feldman, H.C.,Ghosh, R.,Auyeung, V.C.,Mueller, J.L.,Kim, J.H.,Potter, Z.E.,Vidadala, V.N.,Perera, B.G.K.,Olivier, A.,Backes, B.J.,Zikherman, J.,Papa, F.R.,Maly, D.J.
ATP-competitive partial antagonists of the IRE1 alpha RNase segregate outputs of the UPR.
Nat.Chem.Biol., 17:1148-1156, 2021

PubMed Abstract: The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

PubMed: 34556859
DOI: 10.1038/s41589-021-00852-0

Experimental method

X-RAY DIFFRACTION (1.85 Å)