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TitleSignal peptide mimicry primes Sec61 for client-selective inhibition.
Journal, issue, pagesNat Chem Biol, Vol. 19, Issue 9, Page 1054-1062, Year 2023
Publish dateMay 11, 2023
AuthorsShahid Rehan / Dale Tranter / Phillip P Sharp / Gregory B Craven / Eric Lowe / Janet L Anderl / Tony Muchamuel / Vahid Abrishami / Suvi Kuivanen / Nicole A Wenzell / Andy Jennings / Chakrapani Kalyanaraman / Tomas Strandin / Matti Javanainen / Olli Vapalahti / Matthew P Jacobson / Dustin McMinn / Christopher J Kirk / Juha T Huiskonen / Jack Taunton / Ville O Paavilainen /
PubMed AbstractPreventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. ...Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
External linksNat Chem Biol / PubMed:37169961 / PubMed Central
MethodsEM (single particle)
Resolution3.2 Å
Structure data

14776

7zl3

EMDB-14776, PDB-7zl3:
Signal peptide mimicry primes Sec61 for client-selective inhibition
Method: EM (single particle) / Resolution: 3.2 Å

Source
  • ovis aries (sheep)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Sec61 Translocon / cryoEM / Protein biogenesis

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