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The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects
Open accessAbstract
H-Ras, K-Ras, and N-Ras are small GTPases that are important in the control of cell proliferation, differentiation, and survival, and their mutants occur frequently in human cancers. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras isoforms. Because of their very high sequence identity, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We show here that this is not a valid assumption. Using enzyme kinetic assays under identical conditions, we observed clear differences between the three isoforms in intrinsic catalysis of GTP by Ras in the absence and presence of the Ras-binding domain (RBD) of the c-Raf kinase protein (Raf-RBD). Given their identical active sites, isoform G-domain differences must be allosteric in origin, due to remote isoform-specific residues that affect conformational states. We present the crystal structure of N-Ras bound to a GTP analogue and interpret the kinetic data in terms of structural features specific for H-, K-, and N-Ras.
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“RAS mutants were once viewed as being ‘locked’ in the GTP-bound ‘on’ state, impervious to GAP-stimulated or intrinsic GTP hydrolysis, and hence undruggable. However, detailed structural and biochemical analyses of various RAS mutants associated with cancer and ‘RASopathies’”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [45]
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“At the cellular level, the isoform specificity to effector proteins is primarily determined via membrane interactions [24], but the differences among RAS isoforms’ absolute effector protein binding affinities rise from allosteric effects [25].”
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“We were unable to crystalize NRas G13D bound to GDP. Hydrolysis assays to determine rate constants—Hydrolysis of GTP was measured by production of radioactive inorganic phosphate from γ32P-GTP (Perkin Elmer) loaded Ras proteins, as previously published (Johnson et al., 2017).”
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KRAS G12C Mutations in NSCLC: From Target to Resistance
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“With ProtCID, we have identi fi ed an α 4 – α 5 dimer in a crystal of GNP-bound NRAS (PDB: 5UHV [https://doi.org/10.2210/pdb5UHV/ pdb]), that was unrecognized by the authors of this structure 50 .”
BackgroundInfluentialRaf promotes dimerization of the Ras G-domain with increased allosteric connections
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Self-citationKRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation
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“There has been little attempt to study differences in nucleotide exchange and/or GTP hydrolysis rates for the RAS isoforms in their individual contexts; however, one study found that the intrinsic rates of GTP catalysis differed across isoforms using [(32)Pi]GTP single turnover (29).”
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Structure of an inactive conformation of GTP-bound RhoA GTPase
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Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery
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“Growing evidence, however, suggests that KRAS and HRAS behave differently and exhibit mutant-speci fi c distinct conformational features (7, 15, 16).”
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“To identify KRas ligands using SHG, we targeted recombinant His-tagged KRas4b (1-166) carrying the G12D mutation (hereafter referred to as KRas).”
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“The Ras superfamily of membrane-associated small G-proteins is highly conserved and controls a broad range of cellular processes 66 , has inactive and active states that are regulated by a GTPase-activated protein 67 , and has been implicated in cancer 68 .”
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“Mutations in key residues in exon 2 or exon 3 (positions 10–14 [P loop region] and 58–72 [Switch-II region]) affect the GTP-binding site, preventing the conversion of the active RAS-GTP into inactive RAS-GDP, 35,36 leading to the continued activation of its downstream targets MEK1/2 and ERK1/2, 37 promoting cell proli…”
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“The active site for GTP-binding is formed via the P-loop, Switch-I, and switch-II with residue ranges of 10 – 17, 30 – 40, and 60 – 76 amino acids, respectively (Johnson et al., 2017).”
BackgroundWater Distribution within Wild-Type NRas Protein and Q61 Mutants during Unrestrained QM/MM Dynamics
Tichauer, R. H., Favre, G., Cabantous, S., Landa, G., Hémeryck, A., & Brut, M. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.07.042 · Cited by 16
“12–13, 32, 35, and 60–61 from Ras, Arg 789 from GAP, GTP, and a Mg2þ ion with two coordinated water molecules, found in the crystallographic structures of Ras (12,21,39,46) (see Fig.”
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Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants
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Allosteric site variants affect GTP hydrolysis on Ras
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The Importance of Mg 2+ ‐Free State in Nucleotide Exchange of Oncogenic K‐Ras Mutants
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Mechanisms of isoform-specific residue influence on GTP-bound HRas, KRas, and NRas
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Self-citationKinetic and thermodynamic allostery in the Ras protein family
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Reder, H., Wagner, S., Gamerdinger, U., Sandmann, S., Wuerdemann, N., Braeuninger, A., Dugas, M., Gattenloehner, S., Klußmann, J. P., & Wittekindt, C. (2019) · Oral Oncology · doi:10.1016/j.oraloncology.2019.04.013 · Cited by 14
Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces
Ngo, V. A., & Garcı́a, A. E. (2022) · Biophysical Journal · doi:10.1016/j.bpj.2022.04.026 · Cited by 13
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“From these patterns among hotspot variants, we inferred certain amino acid substitutions have the same mechanisms across RAS proteins, while other substitutions are modulated by intrinsic biochemical properties of individual RAS genes [38].”
BackgroundJani, V., Sonavane, U., & Joshi, R. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e36161 · Cited by 12
“Also, Johnson et al. has shown that the three isoforms KRAS, HRAS and NRAS are biochemically distinct [52].”
BackgroundTripathi, S., Dsouza, N. R., Urrutia, R. A., & Zimmermann, M. T. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa972 · Cited by 11
How to make an undruggable enzyme druggable: lessons from ras proteins
Sayyed–Ahmad, A., & Gorfe, A. A. (2020) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2020.05.003 · Cited by 11
Biophysical and Structural Characterization of Novel RAS-Binding Domains (RBDs) of PI3Kα and PI3Kγ
Martinez, N., Thieker, D. F., Carey, L. M., Rasquinha, J. A., Kistler, S., Kuhlman, B. A., & Campbell, S. L. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166838 · Cited by 10
“The PI3K RBDs are more structurally similar to the RALGDS-RBD [34] and bind with similar affinity to RAS relative to the CRAF-RBD [35].”
BackgroundStructures of RGL1 RAS-Association Domain in Complex with KRAS and the Oncogenic G12V Mutant
Eves, B. J., Gebregiworgis, T., Gasmi-Seabrook, G. M. C., Kuntz, D. A., Privé, G. G., Marshall, C. B., & Ikura, M. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167527 · Cited by 10
Nair, V. V., Yin, G., Zhang, J., Hancock, J. F., Campbell, S. L., & Gorfe, A. A. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c01062 · Cited by 9
Ilter, M., Kaşmer, R., Jalalypour, F., Atılgan, C., Topcu, O., Karakaş, N., & Şensoy, Ö. (2022) · eLife · doi:10.7554/elife.79747 · Cited by 7
Tisi, R., Spinelli, M., Palmioli, A., Airoldi, C., Cazzaniga, P., Besozzi, D., Nobile, M. S., Mazzoleni, E., Arnhold, S., GIOIA, L. D., et al. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.625979 · Cited by 8
“, 2019), appropriately modified according to recent data (Johnson et al., 2017; Johnson et al., 2019), predicts the ability of cmp4 to inhibit the proliferation of different Ras-driven cancer cells.”
BackgroundCrystal structure of NRAS Q61K with a ligand-induced pocket near switch II
Gebregiworgis, T., Chan, J. Y.-L., Kuntz, D. A., Privé, G. G., Marshall, C. B., & Ikura, M. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151414 · Cited by 10
Sabt, A., Tawfik, H. O., Khaleel, E. F., Badi, R. M., Ibrahim, H. A. A., Elkaeed, E. B., & Eldehna, W. M. (2024) · Molecular Diversity · doi:10.1007/s11030-023-10777-6 · Cited by 8
“The RAS protein family contains three known human isoforms H-RAS, N-RAS, and K-RAS [8, 9].”
Adeniji, E. A., Olotu, F. A., & Soliman, M. E. S. (2018) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520618666180718110231 · Cited by 7
Predicting X‐ray solution scattering from flexible macromolecules
Zhou, H., Guterres, H., Mattos, C., & Makowski, L. (2018) · Protein Science · doi:10.1002/pro.3508 · Cited by 7
“lated by an allosteric site, which promotes the transition from a disordered T-state to an ordered Rstate conformation conducive to GTP hydrolysis.(25,28)”
BackgroundSelf-citationPrajapati, V., Singh, A. K., Kumar, A. M., Singh, H., Pathak, P., Grishina, M., Kumar, V., Khalilullah, H., Verma, A., & Kumar, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00923a · Cited by 6
Khalid, A. Q., Zaidan, T. N., Bhuvanendran, S., Magalingam, K. B., Mohamedahmed, S. M., Ramdas, P., & Radhakrishnan, A. K. (2024) · Nutrition Reviews · doi:10.1093/nutrit/nuae108 · Cited by 6
Ras Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?
Nair, A., Kubatzky, K. F., & Saha, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126508 · Cited by 7
Yu, R. T. D., & Garcia, R. L. (2020) · Scientific Reports · doi:10.1038/s41598-020-67796-8 · Cited by 6
Adamopoulos, P. G., Tsiakanikas, P., Boti, M. A., & Scorilas, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413298 · Cited by 6
“The allosteric lobe contains hot spots of protein–ligand interactions that bind membrane components and harbors all the differences between the RAS G-domains at the level of primary structure, with a sequence identity of 90% among the allosteric lobes of the three RAS proteins [11,13,14].”
BackgroundNeuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
Zheng, K., Hao, F., Medrano-Garcia, S., Chen, C., Guo, F., Morán-Blanco, L., Rodríguez, S., Torres-Ruiz, R., Peligros, M. I., Vaquero, J., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06029-y · Cited by 5
“All mice were sacri fi ced 28 days after BDL.”
Water in Ras Superfamily Evolution
Marcus, K., & Mattos, C. (2019) · Journal of Computational Chemistry · doi:10.1002/jcc.26060 · Cited by 5
Self-citationCiftci, F. S., & Erman, B. (2026) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.70146 · Cited by 4
Nigam, A., Krishnamoorthy, G. P., Chatila, W. K., Berman, K., Saqcena, M., Walch, H. S., Venkatramani, M., Ho, A. L., Schultz, N. D., Fagin, J. A., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03095-0 · Cited by 5
“Characterization and transfection of “ RASless ” mouse embryonic fi broblasts”
Antipsychotic phenothiazine drugs bind to KRAS in vitro
Wang, X., Gorfe, A. A., & Putkey, J. A. (2021) · Journal of Biomolecular NMR · doi:10.1007/s10858-021-00371-z · Cited by 4
Girard, É., Lopes, P., Spoerner, M., Dhaussy, A., Prangé, T., Kalbitzer, H. R., & Colloc’h, N. (2024) · Chemistry - A European Journal · doi:10.1002/chem.202400304 · Cited by 4
Elucidating Ras protein as a dual therapeutic target for inflammation and cancer: a review
Nandan, P. K., & Jayanthi, S. (2025) · Discover Oncology · doi:10.1007/s12672-025-02783-x · Cited by 4
“It is believed that variable intracellular localization, which favours preferential coupling to particular effector pathways, mediates isoform-specific signalling [51–53] and by unique biochemical characteristics contributed by allosteric lobe sequence differences among each isoform [54].”
PANCS-spec-Binders: A system for rapidly discovering isoform- or epitope-specific binders
Pixley, J. A., Styles, M. J., Aphicho, K., Endres, M., Gade, P., Michalska, K., Joachimiak, A., & Dickinson, B. C. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2531008123 · Cited by 3
Revealing conformational changes of GTP-bound NRAS mutants probed by GaMD and Markov state models
Zhao, L., Wang, J., Ping, H., Yang, W., Cao, H., & Chen, J. (2026) · Physical Chemistry Chemical Physics · doi:10.1039/d5cp04245c · Cited by 3
Knihtila, R., Volmar, A. Y., Meilleur, F., & Mattos, C. (2019) · Acta Crystallographica Section F Structural Biology Communications · doi:10.1107/s2053230x18018125 · Cited by 3
“Furthermore, it has become evident that GTPases are highly allosteric and that the networks across the G-domain play a critical role in the biochemistry of these proteins (Johnson et al., 2017).”
BackgroundSelf-citationGTP-Bound N-Ras Conformational States and Substates Are Modulated by Membrane and Point Mutation
Farcaș, A., & Janosi, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031430 · Cited by 3
“Hence, an order of magnitude fewer crystallographic structures are available for N-Ras (e.g., GDP-bound N-Ras (3CON) [51] and GTP-equivalent GppNHp-bound N-Ras (5UHV) [52]).”
BackgroundMethodProtCID: A data resource for structural information on protein interactionsPreprint
Xu, Q., & Dunbrack, R. L. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/579862 · Cited by 6
Post, J. B., Hami, N., Lohuis, J. O., van de Ven, M., de Korte‐Grimmerink, R., Stangl, C., Stelloo, E., Verlaan-Klink, I., van Rheenen, J., & Snippert, H. J. G. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/860122 · Cited by 3
Metadata
- Authors
- Johnson, C. W., Reid, D., Parker, J. A., Salter, S., Knihtila, R., Kuzmic, P., & Mattos, C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Mattos, Carla
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 292
- Issue
- 31
- Pages
- 12981-12993
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5546037
- OpenAlex
- W2717068414
- Cited by
- 133
- References
- 84
- Citations by year
- 2026: 12 · 2025: 7 · 2024: 15 · 2023: 10 · 2022: 20 · 2021: 18 · 2020: 14 · 2019: 20 · 2018: 12 · 2017: 5
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1517295)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Ras GTPase, KRAS, NRAS, H-Ras, Ras isoforms, allosteric regulation, GTP hydrolysis, enzyme kinetics, Ras-binding domain
- MeSH terms
- Allosteric Regulation, Allosteric Site, Enzyme Stability, Guanosine Triphosphate, Humans, Isoenzymes, Ligands, Membrane Proteins, Models, Molecular, Peptide Fragments, Protein Conformation, Recombinant Proteins, Dinucleoside Phosphates, Proto-Oncogene Proteins p21(ras), Point Mutation, Crystallography, X-Ray, Proto-Oncogene Proteins c-raf, Amino Acid Substitution, Catalytic Domain, GTP Phosphohydrolases, Protein Interaction Domains and Motifs, Biocatalysis
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