Molecular basis for the binding of SH3 ligands with non-peptide elements identified by combinatorial synthesis
Molecular basis for the binding of SH3 ligands with non-peptide elements identified by combinatorial synthesis
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DOI：
10.1016/s1074-5521(96)90134-9
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发表时间：
1996-08-01
影响因子：
--
通讯作者：
Schreiber, SL
中科院分区：
文献类型：
--
作者：
Feng, SB;Kapoor, TM;Schreiber, SL
背景：基于蛋白质结构的组合化学最近被用来发现几种含有Src SH3结构域非肽结合元件的配体。所使用的编码库的形式为Cap- m1 - m2 - m3 - plpplp，其中Cap和Mi是由不同的有机单体组成的。PLPPLP部分提供了一个结构偏置，将非肽片段Cap-M1-M2-M3导向SH3特异性口袋。从110万种不同的化合物中选择了15种配体。选择的结构基础是未知的。结果：通过多维核磁共振光谱测定了从文库中选择的两种含非肽元素配体的Src SH3结构域的溶液结构。这些配体的非肽部分与Src SH3结构域特异性口袋的相互作用不同于与SH3结构域络合的肽。利用这些配体的结构信息设计了不同的同源物，并测量了它们对SH3结构域的亲和力。这些结果为从一个大的配体库中选择一些最优配体提供了结构基础。结论：以蛋白质结构为基础的组合化学循环，然后确定少数最高亲和力配体的结构，为分子识别领域提供了强有力的新工具。
Background: Protein-structure-based combinatorial chemistry has recently been used to discover several ligands containing non-peptide binding elements to the Src SH3 domain. The encoded library used has the form Cap-M1-M2-M3-PLPPLP, in which the Cap and Mi's are composed of a diverse set of organic monomers. The PLPPLP portion provided a structural bias directing the non-peptide fragment Cap-M1-M2-M3 to the SH3 specificity pocket. Fifteen ligands were selected from >1.1 million distinct compounds. The structural basis for selection was unknown.Results: The solution structures of the Src SH3 domain complexed with two ligands containing non-peptide elements selected from the library were determined by multidimensional NMR spectroscopy. The non-peptide moieties of the ligands interact with the specificity pocket of Src SH3 domain differently from peptides complexed with SH3 domains. Structural information about the ligands was used to design various homologs, whose affinities for the SH3 domain were measured. The results provide a structural basis for understanding the selection of a few optimal ligands from a large library.Conclusions: The cycle of protein-structure-based combinatorial chemistry followed by structure determination of the few highest affinity ligands provides a powerful new tool for the field of molecular recognition.