STRUCTURE DETERMINATION OF PROTEINS ASSOCIATED W/ CANCER

与癌症相关的蛋白质的结构测定

• 批准号: 6355158
• 负责人: JAMES D BALEJA
• 金额: $ 2.03万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355158
• 关键词: bacteria; biological products; biomedical resource; proteins

We are determining the three-dimensional structures of several proteins associated with cancer. Certain strains of papillomavirus cause cutaneous warts, whereas several other strains are transmitted sexually and cause genital warts. Infections by roughly 50% of these strains are known to progress to cancer. Greater than 90% of cervical cancer tissue, for example, harbors papillomaviral DNA. One viral protein, the E2 protein, controls viral transcription and has an N-terminal transcriptional activation domain and a C-terminal DNA-binding domain. We are determining the structure for the DNA-binding domain from the human strain, HPV-16 and have collected the data necessary for NMR resonance assignment. A small molecular weight inhibitor for E2 from a different strain of virus (HPV-3 1) has been reported. We have repeated the structure activity relationship determination using the NMR method (SAR by NMR) for our HPV-16 E2 domain. We are also studying two peptides that interact with the E6 protein from the virus. The complex that one of these peptides makes (but not the other) promotes p53 degradation, which presumably leads to cellular proliferation. We hypothesize that since the peptides have similar amino acid sequences, they also have similar three-dimensional structures. The part from each of these peptides that interacts with E6 is observed to be alpha helical, with the amino acid residues most important for binding on one side of the structure. A third kind of protein we are studying is unrelated to papillomavirus, but is involved in many human cancers. The EH domain from RalBP1 is a protein in the Ras signaling pathway downstream from Ras. The EH domain binds calcium using a classical EF-hand motif and appears to interact with proteins associated with cellular sorting. The domain also binds peptides containing a "NPF' motif and we are determining the structure of the EH domain by itself, and in complex with a NPF containing peptide. For the EH domain, we have collected the NMR data required for structure determination.

我们正在确定几个的三维结构 与癌症相关的蛋白质。 某些乳头瘤病毒菌株 导致皮肤疣，而其他几种菌株也会传播 性行为并引起生殖器疣。 其中大约50％的感染 众所周知，菌株会发展为癌症。 大于90％的宫颈 例如，癌组织含有乳头瘤病毒DNA。 一个病毒 蛋白质（E2蛋白）控制病毒转录，并具有 N末端转录激活结构域和C末端 DNA结合域。 我们正在确定 来自人类菌株的DNA结合结构域HPV-16并收集了 NMR共振分配所需的数据。 一个小分子 来自不同病毒菌株的E2的重量抑制剂（HPV-3 1）的重量抑制剂已有 报道了。 我们已经重复了结构活动关系 使用NMR方法（由NMR SAR）确定我们的HPV-16 E2 领域。 我们还研究了两种与E6相互作用的肽 病毒的蛋白质。 这些肽之一的复合物 （但不是另一个）促进p53降解，大概是领导的 到细胞增殖。 我们假设自肽 具有相似的氨基酸序列，它们也具有相似的 三维结构。 这些肽的部分 观察到与E6相互作用的是α螺旋，与氨基相互作用 酸残基最重要的是在结构的一侧结合。 我们研究的第三种蛋白质与 乳头瘤病毒，但参与了许多人类癌症。 EH域 从ralbp1是从下游的RAS信号通路中的一种蛋白质 拉斯。 EH结构域使用经典的EF手基序结合钙，并且 似乎与与细胞分选相关的蛋白质相互作用。 该域还结合了包含“ NPF”基序的肽，我们是 按照复杂的方式确定EH域的结构 与含有肽的NPF。 对于EH领域，我们收集了 结构确定所需的NMR数据。