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Nat Commun ; 11(1): 6387, 2020 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-33318494

RESUMEN

Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.


Asunto(s)
Adenosina Trifosfato/metabolismo , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ribonucleasas/metabolismo , Adenosina Trifosfato/química , Sitio Alostérico/efectos de los fármacos , Cristalografía por Rayos X , Retículo Endoplásmico/metabolismo , Endorribonucleasas/química , Técnicas de Inactivación de Genes , Humanos , Ligandos , Modelos Moleculares , Fosforilación , Conformación Proteica , Pliegue de Proteína , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Multimerización de Proteína , Proteínas Serina-Treonina Quinasas/química , Ribonucleasas/química , Respuesta de Proteína Desplegada
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