2017.09.13 Oncogenic K-Ras signaling and drug discovery
题 目: Oncogenic K-Ras signaling and drug discovery
报告人: Professor Ruth Nussinov
National Cancer Institute at Frederick, U.S.A.
Tel Aviv University, Israel
时 间: 2017年9月13日(周三)13:00-14:00
地 点: 北京大学老化学楼东配楼101报告厅
主持人: 来鲁华 教授
Ras proteins are small GTPases that act as signal transducers between cell surface receptors and several intracellular signaling cascades. KRAS is among the most frequently mutated oncogenes in human tumors. Ras proteins consist of highly homologous catalytic domains, and flexible C-terminal hypervariable regions (HVRs) that differ significantly across Ras isoforms. We have been focusing on key mechanistic questions in oncogenic Ras biology from the structural and signaling standpoints. These include whether Ras’ disordered hypervariable region (HVR) has a role beyond membrane anchoring; Does Ras form dimers, and if so what is their structural landscape and how they help in activating Raf; What are Ras’ redundant pathways and importantly how to identify redundant pathways in cancer; What are the mechanisms of oncogenic mutations; Is RASSF5 - which links Ras and the MAPK pathway to the Hippo pathway - a tumor suppressor or activator as some experiments suggest, and what is the mechanism through which it works; calmodulin - where does it bind and how does it contribute to K-Ras4B cancer development? and more. We believe that structural biology - computations and experiment – is uniquely able to tackle these fascinating and important questions in oncogenic K-Ras signaling and drug discovery.
This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.
Ruth Nussinov is a computational structural biologist at the NCI. Her Ph D thesis proposed the dynamic programming algorithm for the prediction of RNA secondary structure, which is still the primary method toward this aim. She was among the pioneers of DNA sequence analysis, proposed the fundamental concept of Conformational Selection and Population shift, proposed that protein folding and protein binding are similar processes and that proteins whose sequence and global structures differ may still share similar interface architectural motifs. This concept serves as a basis for the prediction of protein interactions. She was also among the first to model amyloid conformations. Currently she focuses on signaling processes in cancer, particularly those Ras-driven. She received her Ph.D. in 1977 from Rutgers University and did post-doctoral work in the Structural Chemistry Department of the Weizmann Institute. Subsequently she was at the Chemistry Department at Berkeley, the Biochemistry Department at Harvard, and a visiting scientist at the NIH. In 1984 she joined the Department of Human Genetics, at the Medical School at Tel Aviv University. In 1985, she accepted a concurrent position at the National Cancer Institute of the NIH, Leidos Biomedical Research, where she is a Senior Principal Scientist and Principle Investigator heading the Computational Structural Biology Section at the NCI. She has authored over 550 scientific papers. She is the Editor-in-Chief in PLOS Computational Biology and Associate Editor and on the Editorial Boards of several journals. She is a frequent speaker in Domestic and International meetings, symposia and academic institutions, won several award and elected fellow of several societies. Her National Cancer Institute website gives further details. https://ccr.cancer.gov/ruth-nussinov.