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Science 18 July 1997:
Vol. 277. no. 5324, pp. 333 - 338
DOI: 10.1126/science.277.5324.333
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Research Articles

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

Klaus Scheffzek, Mohammad Reza Ahmadian, Wolfgang Kabsch, Lisa Wiesmüller, * Alfred Lautwein, dagger Frank Schmitz, Alfred Wittinghofer ddagger

The three-dimensional structure of the complex between human H-Ras bound to guanosine diphosphate and the guanosine triphosphatase (GTPase)-activating domain of the human GTPase-activating protein p120GAP (GAP-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. The structure shows the partly hydrophilic and partly hydrophobic nature of the communication between the two molecules, which explains the sensitivity of the interaction toward both salts and lipids. An arginine side chain (arginine-789) of GAP-334 is supplied into the active site of Ras to neutralize developing charges in the transition state. The switch II region of Ras is stabilized by GAP-334, thus allowing glutamine-61 of Ras, mutation of which activates the oncogenic potential, to participate in catalysis. The structural arrangement in the active site is consistent with a mostly associative mechanism of phosphoryl transfer and provides an explanation for the activation of Ras by glycine-12 and glutamine-61 mutations. Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state.

K. Scheffzek, M. R. Ahmadian, L. Wiesmüller, A. Lautwein, F. Schmitz, and A. Wittinghofer are at the Max-Planck-Institut für molekulare Physiologie, Abteilung Strukturelle Biologie, Rheinlanddamm 201, 44139 Dortmund, Germany. W. Kabsch is at the Max-Planck-Institut für medizinische Forschung, Jahnstrasse 29, 69120 Heidelberg, Germany.
*   Present address: Heinrich Pette Institut für experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, 20251 Hamburg, Germany.

dagger    Present address: Chester Beatty Laboratories, Fulham Road, London SW3 6JB, England.

ddagger    To whom correspondence should be addressed. E-mail: Alfred.Wittinghofer{at}mpi-dortmund.mpg.de

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N. Vitale, W. A. Patton, J. Moss, M. Vaughan, R. J. Lefkowitz, and R. T. Premont (2000)
J. Biol. Chem. 275, 13901-13906
   Abstract »    Full Text »    PDF »
The Mechanism of GTP Hydrolysis by Ras Probed by Fourier Transform Infrared Spectroscopy.
X. Du, H. Frei, and S.-H. Kim (2000)
J. Biol. Chem. 275, 8492-8500
   Abstract »    Full Text »    PDF »
Competition Between Internal AlF4- and Receptor-Mediated Stimulation of Dorsal Raphe Neuron G-Proteins Coupled to Calcium Current Inhibition.
Y. Chen and N. J. Penington (2000)
J Neurophysiol 83, 1273-1282
   Abstract »    Full Text »    PDF »
Stimulation of the GTPase Activity of Translation Elongation Factor G by Ribosomal Protein L7/12.
A. Savelsbergh, D. Mohr, B. Wilden, W. Wintermeyer, and M. V. Rodnina (2000)
J. Biol. Chem. 275, 890-894
   Abstract »    Full Text »    PDF »
Rate acceleration of ATP hydrolysis by F(1)F(o)-ATP synthase.
A. Senior, S Nadanaciva, and J Weber (2000)
J. Exp. Biol. 203, 35-40
   Abstract »
The N-terminal Domain of Pseudomonas aeruginosa Exoenzyme S Is a GTPase-activating Protein for Rho GTPases.
U.-M. Goehring, G. Schmidt, K. J. Pederson, K. Aktories, and J. T. Barbieri (1999)
J. Biol. Chem. 274, 36369-36372
   Abstract »    Full Text »    PDF »
Two New Members of a Family of Ypt/Rab GTPase Activating Proteins. PROMISCUITY OF SUBSTRATE RECOGNITION.
S. Albert and D. Gallwitz (1999)
J. Biol. Chem. 274, 33186-33189
   Abstract »    Full Text »    PDF »
M-Ras, a Widely Expressed 29-kD Homologue of p21 Ras: Expression of a Constitutively Active Mutant Results in Factor-Independent Growth of an Interleukin-3-Dependent Cell Line.
G. R.A. Ehrhardt, K. B. Leslie, F. Lee, J. S. Wieler, and J. W. Schrader (1999)
Blood 94, 2433-2444
   Abstract »    Full Text »    PDF »
Rapid GTP binding and hydrolysis by Gq promoted by receptor and GTPase-activating proteins.
S. Mukhopadhyay and E. M. Ross (1999)
PNAS 96, 9539-9544
   Abstract »    Full Text »    PDF »
Structure of Gialpha 1·GppNHp, Autoinhibition in a Galpha Protein-Substrate Complex.
D. E. Coleman and S. R. Sprang (1999)
J. Biol. Chem. 274, 16669-16672
   Abstract »    Full Text »    PDF »
Guanosine triphosphatase stimulation of oncogenic Ras mutants.
M. R. Ahmadian, T. Zor, D. Vogt, W. Kabsch, Z. Selinger, A. Wittinghofer, and K. Scheffzek (1999)
PNAS 96, 7065-7070
   Abstract »    Full Text »    PDF »
A method for computational combinatorial peptide design of inhibitors of Ras protein.
J. Zeng and H. R. Treutlein (1999)
Protein Eng. Des. Sel. 12, 457-468
   Abstract »    Full Text »    PDF »
Thermodynamic and Kinetic Characterization of the Interaction between the Ras Binding Domain of AF6 and Members of the Ras Subfamily.
T. Linnemann, M. Geyer, B. K. Jaitner, C. Block, H. R. Kalbitzer, A. Wittinghofer, and C. Herrmann (1999)
J. Biol. Chem. 274, 13556-13562
   Abstract »    Full Text »    PDF »
Binding of the Transition State Analog MgADP-fluoroaluminate to F1-ATPase.
S. Nadanaciva, J. Weber, and A. E. Senior (1999)
J. Biol. Chem. 274, 7052-7058
   Abstract »    Full Text »    PDF »


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