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-Structure paper
タイトル | A common mechanism of Sec61 translocon inhibition by small molecules. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 19, Issue 9, Page 1063-1071, Year 2023 |
掲載日 | 2023年5月11日 |
著者 | Samuel Itskanov / Laurie Wang / Tina Junne / Rumi Sherriff / Li Xiao / Nicolas Blanchard / Wei Q Shi / Craig Forsyth / Dominic Hoepfner / Martin Spiess / Eunyong Park / |
PubMed 要旨 | The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural ...The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design. |
リンク | Nat Chem Biol / PubMed:37169959 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.54 - 3.4 Å |
構造データ | EMDB-27581, PDB-8dnv: EMDB-27582, PDB-8dnw: EMDB-27583, PDB-8dnx: EMDB-27584, PDB-8dny: EMDB-27585, PDB-8dnz: EMDB-27586, PDB-8do0: EMDB-27587, PDB-8do1: EMDB-27588, PDB-8do2: EMDB-27589, PDB-8do3: EMDB-29608: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by eeyarestatin I EMDB-29609: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by cotransin EMDB-29610: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by apratoxin F EMDB-29611: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) in a partially-open apo state (Class 1) EMDB-29612: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) in a partially-open apo state (Class 2) EMDB-29613: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by decatransin EMDB-29614: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by ipomoeassin F (Class 1) EMDB-29616: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by cyclotriazadisulfonamide (CADA) EMDB-29617: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by mycolactone EMDB-29635: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by ipomoeassin F (Class 2) |
化合物 | ChemComp-Q6B: ChemComp-HOH: ChemComp-SXF: ChemComp-SXU: ChemComp-SWR: |
由来 |
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キーワード | PROTEIN TRANSPORT/INHIBITOR / translocon / inhibitor / protein translocation / PROTEIN TRANSPORT / PROTEIN TRANSPORT-INHIBITOR complex / decatransin |