CRYSTALLOGRAPHY OF HETEROTRIMERIC G PROTEIN COMPLEXES W/ REGULATORS & EFFECTORS

具有调节剂的异三聚 G 蛋白复合物的晶体学

• 批准号: 6667822
• 负责人: Stephen R Sprang
• 金额: $ 14.27万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667822
• 关键词: bioimaging /biomedical imaging; biological products; biomedical resource; proteins; radiography; structural biology

Data collected at MacCHESS under express mode proposal EM188 were used in the structure determination of the DPC4 and retinoblastoma (Rb) tumor suppressor proteins. DPC4 (now also known as Smad4) signals from TGFb superfamily receptor Ser/Thr protein kinases at the cell surface to the nucleus through homo- and hetero-oligomeric interactions. The crystal structure of the C-terminal domain (CTD) of DPC4, determined at 2.0
resolution, revelas that the DPC4-CTD forms a crystallographic trimer through a conserved protein-protein interface to which the majority of the tumor-derived missense mutations map. We showed that these mutations disrupt homo-oligomerization in vitro and in vivo, and suggested the hypothesis that the trimeric assembly of the Smad4/DPC4-CTD is a critical function in signaling that is targeted by tumorigenic mutations. Because our paper describing the DPC4 structure (1) went in press while we were collecting data at MacCHESS, it only describes a 2.5
-refined structure. The coordinates submitted to the Brookhaven Protein Data Bank were refined using the 2.0
data collected at MacCHESS. The retinoblastoma tumor suppressor, which in most human cancers is inactivated by mutations, is instead inactivated by the human papilloma virus E7 oncoprotein in cervical cancer. The crystal structure of Rb bound to a nine residue E7 peptide containing the LxCxE motif, shared by other Rb-bidning viral and cellular proteins, was determined at 1.85
resolution (2). The structure shows that the LxCxE peptide binds a highly conserved groove on the B box or the interface with the A box, which the structure shows is required for the stable folding of the B box.

EM188在MacChess收集的MacChess的数据为 用于DPC4和视网膜母细胞瘤的结构测定 （RB）肿瘤抑制蛋白。 DPC4（现在也称为SMAD4） 来自TGFB超家族受体SER/THR蛋白激酶的信号 细胞表面通过同型和异源物体到达核的细胞表面 互动。 C末端结构域（CTD）的晶体结构 DPC4，以2.0分辨率确定，Revelas是DPC4-CTD形成的 通过保守蛋白质蛋白的晶体学三聚体 大多数肿瘤衍生的错过的界面 突变图。 我们表明这些突变破坏了 体外和体内均聚物化，并建议 假设SMAD4/DPC4-CTD的三聚合物组装是一个 由肿瘤的靶向信号的关键功能 突变。 因为我们描述DPC4结构（1）的论文进行了 在我们在MacChess收集数据的同时，它仅描述 2.5改良的结构。 提交给布鲁克黑文的坐标 使用收集的2.0数据来完善蛋白质数据库 MacChess。 视网膜母细胞瘤肿瘤抑制剂，在大多数人中 癌症被突变灭活，而是被癌症灭活 宫颈癌中的人乳头状瘤病毒E7癌蛋白。 水晶 RB结合到九个残基E7肽的结构 LXCXE基序，由其他RB的病毒和细胞蛋白共享， 以1.85分辨率（2）确定。 结构表明 LXCXE肽在B框或 与A框的接口，结构显示的框架是必需的 B盒的稳定折叠。