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Small molecule inhibitor binds to NOD-like receptor family pyrin domain containing 3 and prevents inflammasome activation.
Lackner, Angela; Cabral, Julia Elise; Qiu, Yanfei; Zhou, Haitian; Leonidas, Lemuel; Pham, Minh Anh; Macapagal, Alijah; Lin, Sophia; Armanus, Emy; McNulty, Reginald.
Afiliación
  • Lackner A; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Cabral JE; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Qiu Y; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Zhou H; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Leonidas L; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Pham MA; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Macapagal A; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Lin S; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • Armanus E; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • McNulty R; Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
iScience ; 27(8): 110459, 2024 Aug 16.
Article en En | MEDLINE | ID: mdl-39104412
ABSTRACT
Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation. The fold of NLRP3 pyrin domain contains amino acids and a protein fold similar to hOGG1. Amino acids that enable hOGG1 to bind and cleave oxidized DNA are conserved in NLRP3. We found NLRP3 could bind and cleave oxidized guanine within mitochondrial DNA. The binding of oxidized DNA to NLRP3 was prevented by small molecule drugs which also inhibit hOGG1. These same drugs also inhibited inflammasome activation. Elucidating this mechanism will enable the design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1ß (IL-1ß) production in macrophages.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos