Implications of the Essential Role of Small Molecule Ligand Binding Pockets in Protein-Protein Interactions.
Implications of the Essential Role of Small Molecule Ligand Binding Pockets in Protein-Protein Interactions.
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DOI：
10.1021/acs.jpcb.2c04525
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发表时间：
2022-09-15
影响因子：
3.3
通讯作者：
Zhou, Hongyi
中科院分区：
文献类型：
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作者：
Skolnick, Jeffrey;Zhou, Hongyi
蛋白质-蛋白质相互作用（PPI）和蛋白质-代谢物相互作用在许多生化过程中起着关键作用，但它们通常被视为独立的。然而，小分子药物成功抑制PPI的事实表明，结合小分子和PPI的蛋白质口袋之间存在更深层次的关系。我们证明，2/3的PPI接口，包括抗体-表位接口，包含至少一个重要的小分子配体结合口袋。在涉及数百个突变的50种不同蛋白质-蛋白质相互作用的代表性文库中，>75%的热点残基与小分子配体结合口袋重叠。因此，配体结合口袋在PPI中发挥重要作用。在代表性的情况下，参与不同多聚体相互作用但共享相同口袋的进化无关单体被预测为结合相同的代谢物/药物;这些结果通过PDB中的实例得到证实。因此，代谢物的结合可以改变单体和多聚体之间的平衡。PPI平衡的这种隐式耦合，称为“代谢缠结”，被成功地用于表明不直接相互作用的蛋白质多聚体之间的新的功能关系。因此，目前的工作提供了一种方法来统一代谢组学和蛋白质相互作用组学。
Protein–protein interactions (PPIs) and protein–metabolite interactions play a key role in many biochemical processes, yet they are often viewed as being independent. However, the fact that small molecule drugs have been successful in inhibiting PPIs suggests a deeper relationship between protein pockets that bind small molecules and PPIs. We demonstrate that 2/3 of PPI interfaces, including antibody–epitope interfaces, contain at least one significant small molecule ligand binding pocket. In a representative library of 50 distinct protein–protein interactions involving hundreds of mutations, >75% of hot spot residues overlap with small molecule ligand binding pockets. Hence, ligand binding pockets play an essential role in PPIs. In representative cases, evolutionary unrelated monomers that are involved in different multimeric interactions yet share the same pocket are predicted to bind the same metabolites/drugs; these results are confirmed by examples in the PDB. Thus, the binding of a metabolite can shift the equilibrium between monomers and multimers. This implicit coupling of PPI equilibria, termed “metabolic entanglement”, was successfully employed to suggest novel functional relationships among protein multimers that do not directly interact. Thus, the current work provides an approach to unify metabolomics and protein interactomics.
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影响因子：
2.8
作者：
Aulova KS;Urusov AE;Toporkova LB;Sedykh SE;Shevchenko YA;Tereshchenko VP;Sennikov SV;Budde T;Meuth SG;Orlovskaya IA;Nevinsky GA
通讯作者：
Nevinsky GA
人类补体C8的结构，这是膜攻击的前体。
影响因子：
5.6
作者：
Bubeck D;Roversi P;Donev R;Morgan BP;Llorca O;Lea SM
通讯作者：
Lea SM
DOI：
10.1292/jvms.22-0191
发表时间：
2022-08-01
期刊：
The Journal of veterinary medical science
影响因子：
--
作者：
通讯作者：
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影响因子：
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作者：
Arkin MR;Tang Y;Wells JA
通讯作者：
Wells JA
影响因子：
16.2
作者：
Casellini, Carolina M.;Barlow, Patricia M.;Vinik, Aaron I.
通讯作者：
Vinik, Aaron I.