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-Structure paper
タイトル | De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex. |
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ジャーナル・号・ページ | Sci Adv, Vol. 7, Issue 49, Page eabg4007, Year 2021 |
掲載日 | 2021年12月3日 |
著者 | Kai-En Chen / Qian Guo / Timothy A Hill / Yi Cui / Amy K Kendall / Zhe Yang / Ryan J Hall / Michael D Healy / Joanna Sacharz / Suzanne J Norwood / Sachini Fonseka / Boyang Xie / Robert C Reid / Natalya Leneva / Robert G Parton / Rajesh Ghai / David A Stroud / David P Fairlie / Hiroaki Suga / Lauren P Jackson / Rohan D Teasdale / Toby Passioura / Brett M Collins / |
PubMed 要旨 | The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson’s disease, while viral and ...The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function, we have created a novel series of macrocyclic peptides that bind retromer with high affinity and specificity. Crystal structures show that most of the cyclic peptides bind to Vps29 via a Pro-Leu–containing sequence, structurally mimicking known interactors such as TBC1D5 and blocking their interaction with retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting retromer. Last, tagged peptides can be used to probe the cellular localization of retromer and its functional interactions in cells, providing novel tools for studying retromer function. |
リンク | Sci Adv / PubMed:34851660 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 1.58 - 5.9 Å |
構造データ | EMDB-24963: EMDB-24964: PDB-6xs5: PDB-6xs7: PDB-6xs8: PDB-6xs9: PDB-6xsa: |
化合物 | ChemComp-GOL: ChemComp-FMT: ChemComp-HOH: ChemComp-MLI: ChemComp-O4B: ChemComp-SO4: |
由来 |
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キーワード | PROTEIN TRANSPORT/INHIBITOR / Vps29 / Retromer / Endosome / Protein transport / cyclic peptide / inhibitor / PROTEIN TRANSPORT-INHIBITOR complex |