Ras Conformational Ensembles, Allostery, and Signaling

The phosphoinositide 3-kinase pathway

Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works

<i>ras</i> GENES

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The GTPase superfamily: conserved structure and molecular mechanism

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The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330 · see citing works

Targeting RAS signalling pathways in cancer therapy

Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,262 · see citing works

The Energy Landscapes and Motions of Proteins

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Targeting the phosphoinositide 3-kinase pathway in cancer

Liu, P., Cheng, H.-L. M., Roberts, T. M., & Zhao, J. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2926 · Cited by 2,722 · see citing works

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works

Small GTP-Binding Proteins

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COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

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A Comprehensive Survey of Ras Mutations in Cancer

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The role of dynamic conformational ensembles in biomolecular recognition

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Drugging the undruggable RAS: Mission Possible?

Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works

Mammalian Ras interacts directly with the serine/threonine kinase Raf.

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GEFs and GAPs: Critical Elements in the Control of Small G Proteins

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RAS oncogenes: the first 30 years

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The Guanine Nucleotide-Binding Switch in Three Dimensions

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RAS oncogenes: weaving a tumorigenic web

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Model Systems, Lipid Rafts, and Cell Membranes

Simons, K., & Vaz, W. L. C. (2004) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.32.110601.141803 · Cited by 1,671 · see citing works

Regulation of Phosphoinositide-Specific Phospholipase C

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Hyperactive Ras in developmental disorders and cancer

Schubbert, S., Shannon, K., & Bollag, G. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2109 · Cited by 1,583 · see citing works

The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants

Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works

Ras oncogenes: split personalities

Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · see citing works

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch, W. (2000) · Biochemical Journal · doi:10.1042/bj3510289 · Cited by 1,443 · see citing works

The ensemble nature of allostery

Motlagh, H. N., Wrabl, J. O., Li, J., & Hilser, V. J. (2014) · Nature · doi:10.1038/nature13001 · Cited by 1,247 · see citing works

Regulation of Small GTPases by GEFs, GAPs, and GDIs

Cherfils, J., & Zeghouf, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00003.2012 · Cited by 1,245 · see citing works

A Cytoplasmic Protein Stimulates Normal N- <i>ras</i> p21 GTPase, But Does Not Affect Oncogenic Mutants

Trahey, M., & McCormick, F. (1987) · Science · doi:10.1126/science.2821624 · Cited by 1,211 · see citing works

Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine

Walker, E. H., Pacold, M. E., Perišić, O., Stephens, L., Hawkins, P. T., Wymann, M. P., & Williams, R. L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00089-4 · Cited by 1,211 · see citing works

Targeting RAS–ERK signalling in cancer: promises and challenges

Samatar, A. A., & Poulikakos, P. I. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4281 · Cited by 1,163 · see citing works

Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes.

Gohlke, H., Kiel, C., & Case, D. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00610-7 · Cited by 1,087 · see citing works

Increasing complexity of Ras signaling

Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J., & Der, C. J. (1998) · Oncogene · doi:10.1038/sj.onc.1202174 · Cited by 1,079 · see citing works

Refined crystal structure of the triphosphate conformation of H‐ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis.

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Molecular Switch for Signal Transduction: Structural Differences Between Active and Inactive Forms of Protooncogenic ras Proteins

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A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane

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Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1

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Ras proteins: different signals from different locations

Hancock, J. F. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1105 · Cited by 856 · see citing works

Blocking Oncogenic Ras Signaling for Cancer Therapy

Adjei, A. A. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.14.1062 · Cited by 831 · see citing works

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

Holderfield, M. T., Deuker, M. M., McCormick, F. P., & McMahon, M. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3760 · Cited by 828 · see citing works

Human RAS Superfamily Proteins and Related GTPases

Colicelli, J. (2004) · Science s STKE · doi:10.1126/stke.2502004re13 · Cited by 828 · see citing works

Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

Vigil, D., Cherfils, J., Rossman, K. L., & Der, C. J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2960 · Cited by 816 · see citing works

The structural basis of the activation of Ras by Sos

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Human Sos1: a Guanine Nucleotide Exchange Factor for Ras that Binds to GRB2

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Dragging ras back in the ring

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Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786 · see citing works

Understanding Ras: ‘it ain’t over ’til it’s over’

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Allostery in Disease and in Drug Discovery

Nussinov, R., & Tsai, C. (2013) · Cell · doi:10.1016/j.cell.2013.03.034 · Cited by 764 · see citing works

RAS Interaction with PI3K: More Than Just Another Effector Pathway

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Endomembrane Trafficking of Ras

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The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches

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Direct visualization of Ras proteins in spatially distinct cell surface microdomains

Prior, I. A., Muncke, C., Parton, R. G., & Hancock, J. F. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200209091 · Cited by 735 · see citing works

Ras history: The saga continues

Cox, A. D., & Der, C. J. (2010) · Small GTPases · doi:10.4161/sgtp.1.1.12178 · Cited by 706 · see citing works

KRAS: feeding pancreatic cancer proliferation

Bryant, K. L., Mancias, J. D., Kimmelman, A. C., & Der, C. J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.004 · Cited by 675 · see citing works

Multiple ras functions can contribute to mammalian cell transformation

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Folding funnels, binding funnels, and protein function

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The 2.2 Å crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with RaplA and a GTP analogue

Nassar, N. N., Horn, G., Herrmann, C., Scherer, A., McCormick, F. P., & Wittinghofer, A. (1995) · Nature · doi:10.1038/375554a0 · Cited by 631 · see citing works

Accessing protein conformational ensembles using room-temperature X-ray crystallography

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Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

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Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ

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Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling

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Folding and binding cascades: Dynamic landscapes and population shifts

Kumar, S., Ma, B., Tsai, C., Sinha, N., & Nussinov, R. (2000) · Protein Science · doi:10.1110/ps.9.1.10 · Cited by 595 · see citing works

Ras signalling on the endoplasmic reticulum and the Golgi

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Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice

Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E. L., Stamp, G., Alitalo, K. K., & Downward, J. (2007) · Cell · doi:10.1016/j.cell.2007.03.051 · Cited by 589 · see citing works

The p21 ras C-terminus is required for transformation and membrane association

Willumsen, B. M., Christensen, A., Hubbert, N. L., Papageorge, A. G., & Lowy, D. R. (1984) · Nature · doi:10.1038/310583a0 · Cited by 584 · see citing works

The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

Huang, C., Mandelker, D. L., Schmidt‐Kittler, O., Samuels, Y., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Gabelli, S. B., & Amzel, L. M. (2007) · Science · doi:10.1126/science.1150799 · Cited by 564 · see citing works

Regulating the regulator: post-translational modification of RAS

Ahearn, I. M., Haigis, K. M., Bar‐Sagi, D., & Philips, M. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3255 · Cited by 557 · see citing works

An Unidentified Virus which causes the Rapid Production of Tumours in Mice

Harvey, J. J. (1964) · Nature · doi:10.1038/2041104b0 · Cited by 554 · see citing works

Three-Dimensional Structure of an Oncogene Protein: Catalytic Domain of Human c-H- ras P21

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Oncogenic KRAS signalling in pancreatic cancer

EŞER, S., Schnieke, A., Schneider, G., & Saur, D. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.215 · Cited by 506 · see citing works

Guanosine Triphosphatase Activating Protein (GAP) Interacts with the p21 ras Effector Binding Domain

Adari, H. Y., Lowy, D. R., Willumsen, B. M., Der, C. J., & McCormick, F. P. (1988) · Science · doi:10.1126/science.2833817 · Cited by 506 · see citing works

G-protein signaling: back to the future

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The challenge of lipid rafts

PIKE, L. J. (2008) · Journal of Lipid Research · doi:10.1194/jlr.r800040-jlr200 · Cited by 498 · see citing works

Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

Sun, Q., Burke, J. P., Phan, J., Burns, M. C., Olejniczak, E. T., Waterson, A. G., Lee, T., Rossanese, O. W., & Fesik, S. W. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201201358 · Cited by 490 · see citing works

Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS

Margarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar‐Sagi, D., & Kuriyan, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00149-1 · Cited by 486 · see citing works

H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton

Plowman, S. J., Muncke, C., Parton, R. G., & Hancock, J. F. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504114102 · Cited by 468 · see citing works

Ras effectors

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Structure-Function Relationships of the G Domain, a Canonical Switch Motif

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Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains

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The role of lipid rafts in T cell antigen receptor (TCR) signalling

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Localization of Epidermal Growth Factor-stimulated Ras/Raf-1 Interaction to Caveolae Membrane

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Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms

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p110δ, a novel phosphoinositide 3-kinase in leukocytes

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Multiple diverse ligands binding at a single protein site: A matter of pre‐existing populations

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GTPase-activating proteins: Helping hands to complement an active site

Scheffzek, K., Ahmadian, M. R., & Wittinghofer, A. (1998) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01224-9 · Cited by 410 · see citing works

Signaling Interplay in Ras Superfamily Function

Mitin, N., Rossman, K. L., & Der, C. J. (2005) · Current Biology · doi:10.1016/j.cub.2005.07.010 · Cited by 402 · see citing works

A Unified View of “How Allostery Works”

Tsai, C.-J., & Nussinov, R. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003394 · Cited by 401 · see citing works

Digital signaling and hysteresis characterize Ras activation in lymphoid cells.

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Three-dimensional structures of H-ras p21 mutants: Molecular basis for their inability to function as signal switch molecules

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Tethering: Fragment-Based Drug Discovery

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Cholesterol Depletion of Caveolae Causes Hyperactivation of Extracellular Signal-related Kinase (ERK)

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RAF protein-serine/threonine kinases: Structure and regulation

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Stimulation of Membrane Ruffling and MAP Kinase Activation by Distinct Effectors of RAS

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Single-molecule imaging analysis of Ras activation in living cells

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Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras

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Folding and binding cascades: Shifts in energy landscapes

Tsai, C.-J., Ma, B., & Nussinov, R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.9970 · Cited by 365 · see citing works

Phospholipase Cϵ: a novel Ras effector

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Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox, A. D., Der, C. J., & Philips, M. R. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3214 · Cited by 351 · see citing works

Quantitative Analysis of the Complex between p21 and the Ras-binding Domain of the Human Raf-1 Protein Kinase

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Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival

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A model for RAS mutation patterns in cancers: finding the sweet spot

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The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

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The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects

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Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D

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Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs

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Dynamic Protein Allosteric Regulation and Disease

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Developments in integrative modeling with dynamical interfaces

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Data from Delineating the RAS Conformational Landscape

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Asef is a Cdc42-specific guanine nucleotide exchange factor

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SmgGDS displays differential binding and exchange activity towards different Ras isoforms

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Quantitative Analysis of the Effect of Phosphoinositide Interactions on the Function of Dbl Family Proteins

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Conformational Transitions in Switch Regions of the Ras-Like GTPase Rab1B Studied by Free Energy Simulations

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Studies of Hemoglobin and Allosteric Enzymes Under Artificial Conformational Constraints

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