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Nakamura, T. ; Mishima, E. ; Yamada, N. ; Mourao, A. ; Trümbach, D. ; Doll, S. ; Wanninger, J. ; Lytton, E. ; Sennhenn, P.* ; Nishida Xavier da Silva, T.* ; Angeli, J.P.F.* ; Sattler, M. ; Proneth, B. ; Conrad, M.

Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation.

Nat. Struct. Mol. Biol. 30, 1806-1815 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 1545-9993
e-ISSN 1545-9985
Zeitschrift Nature Structural & Molecular Biology
Quellenangaben Band: 30, Heft: 11, Seiten: 1806-1815 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Institute of Structural Biology (STB)