Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors
| Autor: | Michael Prakesch, Rima Al-awar, Kenneth Lee, Lynn Lehmann, Gennadiy Poda, Danka Vuga, David Chiovitti, Colleen Schweitzer, Marella D. Canny, Julie L. Lucas, John B. Patterson, Nero Thevakumaran, Andras Toro, Nicole M. Duffy, Qingping Zeng, Igor Kurinov, Daniel Durocher, David Uehling, Victor Tam, Brian J. Wilson, Manisha Talukdar, Mario Sanches, Frank Sicheri |
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| Rok vydání: | 2014 |
| Předmět: |
RNase P
Protein Conformation Morpholines Endoribonuclease DNA Mutational Analysis General Physics and Astronomy CD59 Antigens Regulatory Factor X Transcription Factors Biology Protein Serine-Threonine Kinases Crystallography X-Ray General Biochemistry Genetics and Molecular Biology Article Small Molecule Libraries 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Protein structure Ribonucleases Coumarins Catalytic Domain Cell Line Tumor Structure–activity relationship Humans Binding site Enzyme Inhibitors 030304 developmental biology 0303 health sciences Aldehydes Multidisciplinary Binding Sites Molecular Structure Endoplasmic reticulum Membrane Proteins General Chemistry Small molecule DNA-Binding Proteins Biochemistry 030220 oncology & carcinogenesis Benzaldehydes Unfolded protein response Plasmacytoma Transcription Factors |
| Zdroj: | Nature communications |
| ISSN: | 2041-1723 |
| Popis: | Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design. |
| Databáze: | OpenAIRE |
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