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Discovery and characterization of cyclic peptides selective for the C-terminal bromodomains of BET family proteins
Structure ( IF 5.7 ) Pub Date : 2023-06-02 , DOI: 10.1016/j.str.2023.05.009
Charlotte Franck 1 , Karishma Patel 2 , Louise J Walport 3 , Mary Christie 2 , Alexander Norman 1 , Toby Passioura 4 , Hiroaki Suga 5 , Richard J Payne 1 , Joel P Mackay 2
Affiliation  

DNA-encoded cyclic peptide libraries can yield high-potency, high-specificity ligands against target proteins. We used such a library to seek ligands that could distinguish between paralogous bromodomains from the closely related bromodomain and extra-terminal domain family of epigenetic regulators. Several peptides isolated from a screen against the C-terminal bromodomain of BRD2, together with new peptides discovered in previous screens against the corresponding domain from BRD3 and BRD4, bound their targets with nanomolar and sub-nanomolar affinities. X-ray crystal structures of several of these bromodomain-peptide complexes reveal diverse structures and binding modes, which nevertheless display several conserved features. Some peptides demonstrate significant paralog-level specificity, although the physicochemical explanations for this specificity are often not clear. Our data demonstrate the power of cyclic peptides to discriminate between very similar proteins with high potency and hint that differences in conformational dynamics might modulate the affinity of these domains for particular ligands.



中文翻译:

对 BET 家族蛋白 C 端溴结构域具有选择性的环肽的发现和表征

DNA 编码的环肽文库可以产生针对靶蛋白的高效、高特异性配体。我们使用这样的库来寻找可以区分旁系同源溴结构域与密切相关的溴结构域和表观遗传调节因子的末端外结构域家族的配体。从针对 BRD2 C端溴结构域的筛选中分离出的几种肽,以及之前针对 BRD3 和 BRD4 相应结构域的筛选中发现的新肽,以纳摩尔和亚纳摩尔亲和力结合其靶标。这些溴结构域-肽复合物中的几种的X射线晶体结构揭示了不同的结构和结合模式,但仍显示出一些保守的特征。一些肽表现出显着的旁系同源水平特异性,尽管这种特异性的物理化学解释通常不清楚。我们的数据证明了环肽能够高效区分非常相似的蛋白质,并暗示构象动力学的差异可能会调节这些结构域对特定配体的亲和力。

更新日期:2023-06-02
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