A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
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DOI：
10.1021/acscentsci.2c01449
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发表时间：
2023-05-24
影响因子：
18.2
通讯作者：
Arkin, Michelle R.
中科院分区：
文献类型：
--
作者：
Kenanova, Dyana N.;Visser, Emira J.;Virta, Johanna M.;Sijbesma, Eline;Centorrino, Federica;Vickery, Holly R.;Zhong, Mengqi;Neitz, R. Jeffrey;Brunsveld, Luc;Ottmann, Christian;Arkin, Michelle R.
蛋白质-蛋白质相互作用（PPIs）的失调通常会导致疾病。PPI的稳定性直到最近才被系统地用于药物发现，尽管它是一种有选择地靶向内在无序蛋白和枢纽蛋白（如14-3-3）的强大方法，具有多个相互作用伙伴。二硫醚系聚是一种基于位点定向片段的药物发现（FBDD）方法，用于鉴定可逆共价小分子。我们探索了利用枢纽蛋白14-3-3σ发现选择性PPI稳定剂（分子胶）的二硫系聚的范围。我们筛选了从14-3-3客户蛋白ERα、FOXO1、C-RAF、USP8和SOS1衍生的5种具有不同生物学和结构的磷酸肽的14-3-3复合物。在4/5的客户络合物中发现了稳定碎片。这些复合物的结构解析揭示了一些肽的构象适应能力，使生产相互作用与拴链片段。我们验证了八种片段稳定剂，其中六种对一种磷酸肽客户端具有选择性，并在结构上表征了两种非选择性撞击和四种选择性稳定C-RAF或fox01的片段。最有效片段使14-3-3σ/C-RAF磷酸肽亲和力提高430倍。在14-3-3σ中，二硫化物与野生型C38的结合为未来14-3-3/客户稳定剂的优化提供了多样化的结构，并突出了发现分子胶的系统方法。分子胶极大地扩展了可药物靶标空间，包括无序蛋白质和蛋白质复合物。二硫系聚系统地发现不同14-3-3/客户络合物的粘合剂。
Dysregulation of protein–protein interactions (PPIs) commonly leads to disease. PPI stabilization has only recently been systematically explored for drug discovery despite being a powerful approach to selectively target intrinsically disordered proteins and hub proteins, like 14-3-3, with multiple interaction partners. Disulfide tethering is a site-directed fragment-based drug discovery (FBDD) methodology for identifying reversibly covalent small molecules. We explored the scope of disulfide tethering for the discovery of selective PPI stabilizers (molecular glues) using the hub protein 14-3-3σ. We screened complexes of 14-3-3 with 5 biologically and structurally diverse phosphopeptides derived from the 14-3-3 client proteins ERα, FOXO1, C-RAF, USP8, and SOS1. Stabilizing fragments were found for 4/5 client complexes. Structural elucidation of these complexes revealed the ability of some peptides to conformationally adapt to make productive interactions with the tethered fragments. We validated eight fragment stabilizers, six of which showed selectivity for one phosphopeptide client, and structurally characterized two nonselective hits and four fragments that selectively stabilized C-RAF or FOXO1. The most efficacious fragment increased 14-3-3σ/C-RAF phosphopeptide affinity by 430-fold. Disulfide tethering to the wildtype C38 in 14-3-3σ provided diverse structures for future optimization of 14-3-3/client stabilizers and highlighted a systematic method to discover molecular glues. Molecular glues dramatically expand the druggable target space to include disordered proteins and protein complexes. Disulfide tethering systematically discovers glues for diverse 14-3-3/client complexes.
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影响因子：
3.5
作者：
Centorrino, Federica;Ballone, Alice;Ottmann, Christian
通讯作者：
Ottmann, Christian
影响因子：
56.9
作者：
Kim, Minkyu;Park, Jisoo;Bouhaddou, Mehdi;Kim, Kyumin;Rojc, Ajda;Modak, Maya;Soucheray, Margaret;McGregor, Michael J.;O'Leary, Patrick;Wolf, Denise;Stevenson, Erica;Foo, Tzeh Keong;Mitchell, Dominique;Herrington, Kari A.;Munoz, Denise P.;Tutuncuoglu, Beril;Chen, Kuei-Ho;Zheng, Fan;Kreisberg, Jason F.;Diolaiti, Morgan E.;Gordan, John D.;Coppe, Jean-Philippe;Swaney, Danielle L.;Xia, Bing;van 't Veer, Laura;Ashworth, Alan;Ideker, Trey;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
影响因子：
--
作者：
Lodge, Jean M.;Rettenmaier, T. Justin;Mapp, Anna K.
通讯作者：
Mapp, Anna K.
影响因子：
4.2
作者：
Hartman, Alwin M.;Elgaher, Walid A. M.;Hirsch, Anna K. H.
通讯作者：
Hirsch, Anna K. H.
影响因子：
--
作者：
Arkin MR;Tang Y;Wells JA
通讯作者：
Wells JA