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

Scheffzek, Klaus; Ahmadian, Mohammad Reza; Kabsch, Wolfgang; Wiesmüller, Lisa; Lautwein, Alfred; Schmitz, Frank; Wittinghofer, Alfred

doi:10.1126/science.277.5324.333

Cited by 1,543Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesReceptor Mechanisms and Signaling

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

Scheffzek, Klaus, Ahmadian, Mohammad Reza, Kabsch, Wolfgang, Wiesmüller, Lisa, Lautwein, Alfred, Schmitz, Frank, Wittinghofer, Alfred·1997·Science

DOI 10.1126/science.277.5324.333

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Abstract

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 p120 GAP (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.

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Wild-type RAS isoforms have weak intrinsic GTPase activity and can self-inactivate, while RAS-GAPs stimulate this activity dramatically, increasing it fivefold over the intrinsic rate.
“Wild-type RAS isoforms have intrinsic, albeit weak, hydrolytic (GTPase) activity and can, therefore, self-inactivate; however, RAS-GAPs stimulate this activity dramatically11–14. Indeed, the GAPs increase RAS GTPase activity fivefold relative to the intrinsic rate12.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [13]
Most somatic mutations in KRAS impair GTPase function, leading to a persistent increase in RAS-GTP levels.
“most somatic mutations in KRAS impair this GTPase function, leading to a persistent increase in RAS-GTP levels.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [10]

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Authors: Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A.
Affiliations: Max Planck Society (DE)
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.
Corresponding author: Lautwein, Alfred
Wittinghofer, Alfred
ORCID: Scheffzek, Klaus
Ahmadian, Mohammad Reza
Wittinghofer, Alfred
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1997-07-18
Volume: 277
Issue: 5324
Pages: 333-339
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.277.5324.333
OpenAlex: W1992864103
Cited by: 1,543
References: 62
Citations by year: 2026: 43 · 2025: 52 · 2024: 57 · 2023: 44 · 2022: 67 · 2021: 70 · 2020: 61 · 2019: 59 · 2018: 48 · 2017: 55 · 2016: 69 · 2015: 55 · 2014: 61 · 2013: 65 · 2012: 64
FWCI: 23.51
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: Ras, GTPase activation, oncogenic Ras mutations, switch II, transition state, phosphoryl transfer, aluminum fluoride, protein structure
MeSH terms: Amino Acid Sequence, Binding Sites, Catalysis, Cell Transformation, Neoplastic, Enzyme Activation, Fluorides, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Protein Conformation, Proteins, Signal Transduction, Protein Structure, Secondary, Aluminum Compounds, Crystallography, X-Ray, ras Proteins, GTP-Binding Proteins, GTP Phosphohydrolases, GTPase-Activating Proteins, ras GTPase-Activating Proteins

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

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