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Ras proteins: dynamics, membrane organization and ligand binding

Seminar:

Ras proteins: dynamics, membrane organization and ligand binding
Monday, October 28, 2013
2PM – 3PM
POB 6.304

Alemayehu A. Gorfe

The GTPase Ras proteins play a key role in the regulation of cell signaling pathways involved in cell growth and development. Malfunction of Ras proteins is associated with about 20-30% of all human cancers and a variety of developmental disorders. Our group uses multi-resolution molecular simulation techniques to study Ras dynamics, membrane binding and assembly. We leverage insights from these studies, such as the role of allostery and conformational selection, for the design of inhibitors that directl act on Ras. In this presentation I will: (1) talk about how a better understanding of Ras dynamics in different environments can lead to small molecule ligands that directly bind Ras, (2) highlight our recent collaborative efforts with cell biologists and pharmacologists to show for the first time that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras, and (3) briefly describe the role of lipid modification for the assembly and lateral segregation of Ras proteins in membrane domains.

Key references:
1. Prakash, P. and A. A. Gorfe, Lessons from computer simulations of Ras proteins in solution and in membrane. Biochem biophys Acta, 2013. 1830(11): p. 5211-8.
2. Hocker, H.J., et al., Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc Natl Acad Sci U S A, 2013. 110(25): p. 10201-6.
3. Janosi, L., et al., Organization, dynamics, and segregation of Ras nanoclusters in membrane domains. Proc Natl Acad Sci U S A, 2012. 109(21): p. 8097-102.
4. Li, Z., L. Janosi, and A.A. Gorfe, Formation and Domain Partitioning of H-ras Peptide Nanoclusters: Effects of Peptide Concentration and Lipid Composition. J. Am Chem Soc., 2012. 134(41): p. 17278-85.

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