Mol Cancer Res 2015 Apr 7;13(4):595-603. Epub 2015 Jan 7.
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts.
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Biochem J 2016 06 7;473(12):1719-32. Epub 2016 Apr 7.
Cancer and Inflammation Program, National Cancer Institute at Frederick, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Are the dimer structures of active Ras isoforms similar? This question is significant since Ras can activate its effectors as a monomer; however, as a dimer, it promotes Raf's activation and MAPK (mitogen-activated protein kinase) cell signalling. In the present study, we model possible catalytic domain dimer interfaces of membrane-anchored GTP-bound K-Ras4B and H-Ras, and compare their conformations. The active helical dimers formed by the allosteric lobe are isoform-specific: K-Ras4B-GTP favours the α3 and α4 interface; H-Ras-GTP favours α4 and α5. Read More
J Mol Biol 2014 Feb 2;426(3):611-29. Epub 2013 Nov 2.
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA. Electronic address:
Ras GTPase mediates several cellular signal transduction pathways and is found mutated in a large number of cancers. It is active in the GTP-bound state, where it interacts with effector proteins, and at rest in the GDP-bound state. The catalytic domain is tethered to the membrane, with which it interacts in a nucleotide-dependent manner. Read More
Proc Natl Acad Sci U S A 2010 Mar 1;107(11):4931-6. Epub 2010 Mar 1.
Department of Molecular and Structural Biochemistry, North Carolina State University, 128 Polk Hall-CB 7622, Raleigh, NC 27695, USA.
Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. Read More
J Mol Biol 2011 Nov 16;413(4):773-89. Epub 2011 Sep 16.
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the "off" and "on" allosteric states of the GTP-bound form of H-Ras. Read More