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    The Ras-Membrane Interface: Isoform-specific Differences in The Catalytic Domain.
    Mol Cancer Res 2015 Apr 7;13(4):595-603. Epub 2015 Jan 7.
    Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts.
    The small GTPase Ras is mutated in about 20% of human cancers, primarily at active site amino acid residues G12, G13, and Q61. Thus, structural biology research has focused on the active site, impairment of GTP hydrolysis by oncogenic mutants, and characterization of protein-protein interactions in the effector lobe half of the protein. The C-terminal hypervariable region has increasingly gained attention due to its importance in H-Ras, N-Ras, and K-Ras differences in membrane association. A high-resolution molecular view of the Ras-membrane interaction involving the allosteric lobe of the catalytic domain has lagged behind, although evidence suggests that it contributes to isoform specificity. The allosteric lobe has recently gained interest for harboring potential sites for more selective targeting of this elusive "undruggable" protein. The present review reveals critical insight that isoform-specific differences appear prominently at these potentially targetable sites and integrates these differences with knowledge of Ras plasma membrane localization, with the intent to better understand the structure-function relationships needed to design isoform-specific Ras inhibitors.

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    Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers.
    Biochem J 2016 Jun 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
    DRoP: a water analysis program identifies Ras-GTP-specific pathway of communication between membrane-interacting regions and the active site.
    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
    Allosteric modulation of Ras positions Q61 for a direct role in catalysis.
    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
    Analysis of binding site hot spots on the surface of Ras GTPase.
    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