From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.
From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.
复制标题
通过片段连接从 14-3-3 蛋白质-蛋白质相互作用的束缚稳定剂到独立稳定剂。
DOI：
10.1002/anie.202308004
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ottmann,Christian
中科院分区：
文献类型：
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作者：
Visser,EmiraJ;Jaishankar,Priyadarshini;Sijbesma,Eline;Pennings,MarloesAM;Vandenboorn,EdmeeMF;Guillory,Xavier;Neitz,RJeffrey;Morrow,John;Dutta,Shubhankar;Renslo,AdamR;Brunsveld,Luc;Arkin,MichelleR;Ottmann,Christian
蛋白质-蛋白质相互作用（PPI）的小分子稳定化是化学生物学和药物发现中一种有前途的策略。然而，PPI稳定剂的系统发现仍然是一个很大程度上未满足的挑战。在本文中，我们报告了一种靶向14 - 3 - 3和来自雌激素受体α（ERα）蛋白的肽的界面的片段连接方法。两类片段-共价和非共价片段-共结晶并随后连接，从而产生非共价杂交分子，其中原始片段相互作用在很大程度上是保守的。在20种晶体结构的支持下，该初始杂交分子进一步优化，导致14 - 3 - 3/ERα相互作用的选择性25倍稳定化。单个片段、其共晶结构和连接片段的高分辨率结构证明了通过连接至初始栓系片段来开发正构PPI稳定剂的可行策略。
Small‐molecule stabilization of protein‐protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment‐linking approach targeting the interface of 14‐3‐3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co‐crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25‐fold stabilization of the 14‐3‐3/ERα interaction. The high‐resolution structures of both the single fragments, their co‐crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.