通过共价片段作为稳定剂对14-3-3蛋白-蛋白相互作用口袋的探索
Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.
作者信息
Sijbesma Eline, Hallenbeck Kenneth K, Andrei Sebastian A, Rust Reanne R, Adriaans Joris M C, Brunsveld Luc, Arkin Michelle R, Ottmann Christian
机构信息
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco 94134, United States.
出版信息
ACS Med Chem Lett. 2021 May 10;12(6):976-982. doi: 10.1021/acsmedchemlett.1c00088. eCollection 2021 Jun 10.
The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.
系统地发现与蛋白质复合物复合界面结合的功能片段是开发蛋白质-蛋白质相互作用（PPI）的正构稳定剂的关键第一步。我们之前已经表明，二硫键捕获成功地产生了14-3-3与雌激素受体ERα的PPI的共价稳定剂。在这里，我们对复合PPI靶口袋以及与特定子口袋结合的各种片段的分子特征进行了评估。评估构效关系突出了这些共价片段稳定PPI的基本原理，这些片段以“分子胶”作用模式与蛋白质/肽界面处相对较大且暴露的结合口袋结合。
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