6URC

Crystal structure of IRE1a in complex with compound 18

6URC の概要

• エントリーDOI: 10.2210/pdb6urc/pdb
• 分子名称: Serine/threonine-protein kinase/endoribonuclease IRE1, 2-chloro-N-(6-methyl-5-{[3-(2-{[(3S)-piperidin-3-yl]amino}pyrimidin-4-yl)pyridin-2-yl]oxy}naphthalen-1-yl)benzene-1-sulfonamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: kinase, rnase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100417.32

構造登録者

Wallweber, H.H.,Wang, W. (登録日: 2019-10-23, 公開日: 2019-11-06, 最終更新日: 2023-10-11)

主引用文献

Harnoss, J.M.,Le Thomas, A.,Shemorry, A.,Marsters, S.A.,Lawrence, D.A.,Lu, M.,Chen, Y.A.,Qing, J.,Totpal, K.,Kan, D.,Segal, E.,Merchant, M.,Reichelt, M.,Ackerly Wallweber, H.,Wang, W.,Clark, K.,Kaufman, S.,Beresini, M.H.,Laing, S.T.,Sandoval, W.,Lorenzo, M.,Wu, J.,Ly, J.,De Bruyn, T.,Heidersbach, A.,Haley, B.,Gogineni, A.,Weimer, R.M.,Lee, D.,Braun, M.G.,Rudolph, J.,VanWyngarden, M.J.,Sherbenou, D.W.,Gomez-Bougie, P.,Amiot, M.,Acosta-Alvear, D.,Walter, P.,Ashkenazi, A.
Disruption of IRE1 alpha through its kinase domain attenuates multiple myeloma.
Proc. Natl. Acad. Sci. U.S.A., 116:16420-16429, 2019

PubMed Abstract: Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138 plasma cells while sparing CD138 cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.

PubMed: 31371506
DOI: 10.1073/pnas.1906999116

実験手法

X-RAY DIFFRACTION (2.2 Å)