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-Structure paper
タイトル | Signal peptide mimicry primes Sec61 for client-selective inhibition. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 19, Issue 9, Page 1054-1062, Year 2023 |
掲載日 | 2023年5月11日 |
著者 | Shahid 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 要旨 | 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. ...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. |
リンク | Nat Chem Biol / PubMed:37169961 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.2 Å |
構造データ | EMDB-14776, PDB-7zl3: |
由来 |
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キーワード | MEMBRANE PROTEIN / Sec61 Translocon / cryoEM / Protein biogenesis |