Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
J Am Chem Soc. 2012 Jan 11;134(1):103-6. doi: 10.1021/ja2090367. Epub 2011 Dec 14.
Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 Å resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.
Mdm2 是肿瘤抑制蛋白 p53 的主要负调控因子，p53 蛋白在维持基因组完整性方面起着至关重要的作用。p53 的失活是人类癌症中最常见的缺陷。恢复功能性 p53 的 Mdm2-p53 相互作用抑制剂构成了具有新型作用机制的潜在非遗传毒性抗癌药物。我们在这里展示了一个分辨率为 2.0Å 的 Mdm2 蛋白与结合的订书钉 p53 肽的结构。这些肽通过全碳氢 staples 进行构象和蛋白水解稳定，是一类新兴的生物制剂，能够破坏蛋白质-蛋白质相互作用，因此具有广泛的治疗潜力。该结构代表了第一个结合其靶标的 i, i + 7 订书钉肽的晶体结构，揭示了订书钉不仅可以作为被动的构象支撑，还可以与蛋白质表面密切相互作用并增强结合界面。
