olzmannlab.bsky.social
Professor of Molecular Therapeutics and Metabolic Biology at UC Berkeley; Departments of Molecular & Cell Biology and Nutritional Sciences & Toxicology. Lipid droplets, ferroptosis, ubiquitin, drug development.
67 posts
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😂 I’ll take that last piece, please!
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Write a McClintock Letter w @cornellasap.bsky.social - an op-ed in your hometown newspaper that tells your science story & advocates for federal research funding. The goal is to publish ~6/16 (McClintock’s bday). I’m writing one, I'm super pumped! Sign up here: blogs.cornell.edu/asap/events-...
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Indeed! We knew since the 2023 paper that FSEN1 is human specific, but the structure provides the molecular basis. For now, viFSP1 is the best option for inhibition of mouse FSP1.
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Thank you, Micha! 😊
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Thank you, Gisou!! ☺️
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In summary, the cocrystal structure of FSP1 with FSEN1 provides mechanistic insight, explains its species selectivity, and provides a foundation for future medchem efforts. Thank you to our collaborators and also the editor & reviewers for the helpful comments / guidance! 🥳
9/9
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The key role of F360 in FSEN1 binding explains the human specificity of FSEN1, since F360 is a leucine in mouse FSP1. Importantly, mutation of mouse L360 to a phenylalanine enables FSEN1 inhibition.
8/9
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FSEN1 (and CoQ) make important pi-pi stacking interactions with F360 of FSP1 and mutations of this residue block FSEN1 inhibition. This mode of interaction is similar to what was observed in docking studies for iFSP1 with FSP1 (Conrad group).
7/9
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FSEN1 occupies a similar position as previously observed for CoQ1 in the crystal structure of chicken FSP1 (PDB: 7XPI), indicating FSEN1 is a competitive inhibitor.
6/9
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The triazolo-thiazole core along with the attached phenyl group of FSEN1 are buried into the substrate binding pocket of FSP1. This portion of the molecule is conserved in other related FSP1 inhibitors (FSEN1-9).
5/9
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Here, we solved the cocrystal structure of human FSP1 in complex with FSEN1 at 2.01 Å. Electron densities for NADP+, 6-OH-FAD, and FSEN1 are well resolved.
4/9
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We subsequently identified a set of structurally diverse small molecule inhibitors of FSP1 that sensitize a wide variety of cancer cells to ferroptosis. The most potent inhibitor was FSEN1, but the mechanism of FSEN1 inhibition remained unclear.
3/9
www.cell.com/cell-chemica...
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In 2019, we (and the Conrad/Angeli groups) discovered FSP1 as a ferroptosis resistance factor. FSP1 reduces non-mitochondrial CoQ to generate a local radical-trapping antioxidant that blocks lipid peroxidation.
2/9
www.nature.com/articles/s41...
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Thank you, Micha! 😊
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Agree! ☺️
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Very cool study from Raphael Rodriguez and team – "Activation of lysosomal iron triggers ferroptosis in cancer" www.nature.com/articles/s41...
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Congrats on these exciting discoveries! 🤩
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And the fantastic News & Views summary from @mikelangelipid.bsky.social and
@olzmannlab.bsky.social: www.nature.com/articles/d41...
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Come on over, Jesse! ☺️