De novo coiled-coil peptides as scaffolds for disrupting protein-protein interactions.
De novo coiled-coil peptides as scaffolds for disrupting protein-protein interactions.
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DOI：
10.1039/c8sc02643b
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发表时间：
2018-10-21
期刊：
影响因子：
8.4
通讯作者：
Woolfson DN
中科院分区：
文献类型：
--
作者：
Fletcher JM;Horner KA;Bartlett GJ;Rhys GG;Wilson AJ;Woolfson DN
同源和异源二聚体卷曲螺旋作为α-螺旋蛋白结合基序呈递的支架。蛋白质-蛋白质相互作用（PPI）在大多数生物过程中起着关键作用。因此，靶向和破坏PPI的改进方法将为化学生物学提供工具，并为治疗开发提供线索。具有α-螺旋组分的PPI是有吸引力的靶标，因为二级结构已被充分理解，并且可以被模拟或稳定以提供基于小分子和限制性肽的抑制剂。在这里，我们提出了一种针对α-螺旋介导的PPI的策略，该策略利用从头卷曲螺旋组装并使用MCL-1/NOXA-B PPI进行测试。首先，使用计算丙氨酸扫描来识别来自NOXA-B的有助于界面的关键α-螺旋残基。接下来，将这些残基接枝到从头设计的同源二聚体或异源二聚体卷曲螺旋肽的暴露表面上。所得的合成肽在中nM范围内选择性抑制同源MCL-1/BID复合物。此外，异二聚体系统提供控制，因为仅当接枝肽及其设计的配偶体都存在时才发生抑制。这确立了利用以从头卷曲螺旋稳定的肽作为PPI抑制剂的概念证据。这种对超分子组装的依赖为调控引入了新的可能性。
Homo- and hetero-dimeric coiled coils as scaffolds for the presentation of α-helical protein-binding motifs. Protein–protein interactions (PPIs) play pivotal roles in the majority of biological processes. Therefore, improved approaches to target and disrupt PPIs would provide tools for chemical biology and leads for therapeutic development. PPIs with α-helical components are appealing targets given that the secondary structure is well understood and can be mimicked or stabilised to render small-molecule and constrained-peptide-based inhibitors. Here we present a strategy to target α-helix-mediated PPIs that exploits de novo coiled-coil assemblies and test this using the MCL-1/NOXA-B PPI. First, computational alanine scanning is used to identify key α-helical residues from NOXA-B that contribute to the interface. Next, these residues are grafted onto the exposed surfaces of de novo designed homodimeric or heterodimeric coiled-coil peptides. The resulting synthetic peptides selectively inhibit a cognate MCL-1/BID complex in the mid-nM range. Furthermore, the heterodimeric system affords control as inhibition occurs only when both the grafted peptide and its designed partner are present. This establishes proof of concept for exploiting peptides stabilised in de novo coiled coils as inhibitors of PPIs. This dependence on supramolecular assembly introduces new possibilities for regulation and control.
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设计蛋白质 - 蛋白质相互作用的螺旋肽抑制剂。
影响因子：
6.8
作者：
Rezaei Araghi R;Keating AE
通讯作者：
Keating AE
影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
DOI：
10.1002/anie.201410810
发表时间：
2015-03-02
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Barnard A;Long K;Martin HL;Miles JA;Edwards TA;Tomlinson DC;Macdonald A;Wilson AJ
通讯作者：
Wilson AJ
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
DOI：
10.1073/pnas.0701297104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Czabotar, Peter E.;Lee, Erinna F.;Colman, Peter M.
通讯作者：
Colman, Peter M.