The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Data from Delineating the RAS Conformational Landscape
Open accessPreprint — published as 10.1158/0008-5472.can-22-0804 · Paper page
Abstract
Abstract Mutations in RAS isoforms (KRAS, NRAS, and HRAS) are among the most frequent oncogenic alterations in many cancers, making these proteins high priority therapeutic targets. Effectively targeting RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structural catalog of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. Here we present an expanded classification of RAS conformations based on analyses of the catalytic switch 1 (SW1) and switch 2 (SW2) loops. From 721 human KRAS, NRAS, and HRAS structures available in the Protein Data Bank (206 RAS–protein cocomplexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of Y32 in SW1 and Y71 in SW2. Clustering all well-modeled SW1 and SW2 loops using a density-based machine learning algorithm defined additional conformational subsets, some previously undescribed. Three SW1 conformations and nine SW2 conformations were identified, each associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation could be further subdivided on the basis of the hydrogen bond type made between Y32 and the GTP γ-phosphate. Further analysis clarified the catalytic impact of G12D and G12V mutations and the inhibitor chemistries that bind to each druggable RAS conformation. Overall, this study has expanded our understanding of RAS structural biology, which could facilitate future RAS drug discovery. Significance:Analysis of >700 RAS structures helps define an expanded landscape of active, inactive, and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS inhibitor–binding modes.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
(1996) · Cited by 20,179
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808
Stereochemistry of polypeptide chain configurations
Ramachandran, G. N., Ramakrishnan, C., & Sasisekharan, V. (1963) · Journal of Molecular Biology · doi:10.1016/s0022-2836(63)80023-6 · Cited by 3,651
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
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Fpocket: An open source platform for ligand pocket detection
Guilloux, V. L., Schmidtke, P., & Tufféry, P. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-168 · Cited by 1,724
PISCES: a protein sequence culling server
Wang, G., & Dunbrack, R. L. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btg224 · Cited by 1,664
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
The Frequency of Ras Mutations in Cancer
Prior, I. A., Hood, F. E., & Hartley, J. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3682 · Cited by 1,130
The structural basis of the activation of Ras by Sos
Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., & Kuriyan, J. (1998) · Nature · doi:10.1038/28548 · Cited by 799
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
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
Maurer, T., Garrenton, L. S., Oh, A., Pitts, K., Anderson, D. J., Skelton, N. J., Fauber, B. P., Pan, B., Malek, S., Stokoe, D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116510109 · Cited by 618
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
Drugging an undruggable pocket on KRAS
Kessler, D., Gmachl, M., Mantoulidis, A., Martin, L. J., Zoephel, A., Mayer, M., Gollner, A., Covini, D., Fischer, S., Gerstberger, T., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904529116 · Cited by 449
A new clustering of antibody CDR loop conformations
North, B., Lehmann, A., & Dunbrack, R. L. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.10.030 · Cited by 380
Defining a new nomenclature for the structures of active and inactive kinases
Modi, V., & Dunbrack, R. L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814279116 · Cited by 367
Ras Conformational Ensembles, Allostery, and Signaling
Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00542 · Cited by 355
Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336
Dynamic properties of the Ras switch I region and its importance for binding to effectors
Spoerner, M., Herrmann, C., Vetter, I. R., Kalbitzer, H. R., & Wittinghofer, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081441398 · Cited by 324
Inhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283
ProteinsPlus: a web portal for structure analysis of macromolecules
Fährrolfes, R., Bietz, S., Flachsenberg, F., Meyder, A., Nittinger, E., Otto, T., Volkamer, A., & Rarey, M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx333 · Cited by 265
NMR-based functional profiling of RASopathies and oncogenic RAS mutations
Smith, M. J., Neel, B. G., & Ikura, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218173110 · Cited by 257
Allosteric modulation of Ras positions Q61 for a direct role in catalysis
Buhrman, G., Holzapfel, G. A., Fetics, S., & Mattos, C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912226107 · Cited by 246
Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras Proteins
Gorfe, A. A., Grant, B. J., & McCammon, J. A. (2008) · Structure · doi:10.1016/j.str.2008.03.009 · Cited by 216
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Burns, M. C., Sun, Q., Daniels, R. N., Camper, D., Kennedy, J. P., Phan, J., Olejniczak, E. T., Lee, T., Waterson, A. G., Rossanese, O. W., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315798111 · Cited by 199
Tissue-Specific Oncogenic Activity of KRASA146T
Poulin, E. J., Bera, A. K., Lu, J., Lin, Y.-J., Strasser, S. D., Paulo, J. A., Huang, T. Q., Morales, C., Yan, W., Cook, J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1220 · Cited by 197
Tanaka, T. U., Williams, R. L., & Rabbitts, T. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601744 · Cited by 155
Structural Basis for Conformational Dynamics of GTP-bound Ras Protein
Shima, F., Ijiri, Y., Muraoka, S., Liao, J., Ye, M., Araki, M., Matsumoto, K., Yamamoto, N., Sugimoto, T., Yoshikawa, Y., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.125161 · Cited by 148
Jiang, L., Kuhlman, B. A., Kortemme, T., & Baker, D. A. (2005) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20347 · Cited by 139
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C
Zeng, M., Lu, J., Li, L., Feru, F., Quan, C., Gero, T. W., Ficarro, S. B., Xiong, Y., Ambrogio, C., Paranal, R. M., et al. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.06.017 · Cited by 136
Cruz-Migoni, A., Canning, P., Quevedo, C. E., Bataille, C. J. R., Béry, N., Miller, A., Russell, A. J., Phillips, S. E. V., Carr, S. B., & Rabbitts, T. H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811360116 · Cited by 135
Quevedo, C. E., Cruz-Migoni, A., Béry, N., Miller, A., Tanaka, T. U., Petch, D., Bataille, C. J. R., Lee, L. Y. W., Fallon, P. S., Tulmin, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05707-2 · Cited by 134
KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis
Rabara, D., Tran, T. H., Dharmaiah, S., Stephens, R. M., McCormick, F., Simanshu, D. K., & Holderfield, M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908353116 · Cited by 128
Buhrman, G., Foight, G., & Mattos, C. (2007) · Structure · doi:10.1016/j.str.2007.10.011 · Cited by 118
Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States
Gentile, D. R., Rathinaswamy, M. K., Jenkins, M. L., Moss, S. M., Siempelkamp, B. D., Renslo, A. R., Burke, J. E., & Shokat, K. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.025 · Cited by 117
KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe
Bery, N., Legg, S., Debreczeni, J., Breed, J., Embrey, K., Stubbs, C., Kolasinska-Zwierz, P., Barrett, N., Marwood, R., Watson, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10419-2 · Cited by 97
Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange
Guillard, S., Kolasinska-Zwierz, P., Debreczeni, J. E., Breed, J., Zhang, J., Béry, N., Marwood, R., Tart, J., Overman, R., Stocki, P., et al. (2017) · Nature Communications · doi:10.1038/ncomms16111 · Cited by 97
A new clustering and nomenclature for beta turns derived from high-resolution protein structures
Shapovalov, M. V., Vučetić, S., & Dunbrack, R. L. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006844 · Cited by 94
Selective and noncovalent targeting of RAS mutants for inhibition and degradation
Teng, K. W., Tsai, S. T., Hattori, T., Fedele, C., Koide, A., Yang, C., Hou, X., Zhang, Y., Neel, B. G., O’Bryan, J. P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22969-5 · Cited by 89
Johnson, C. W., Lin, Y.-J., Reid, D., Parker, J., Pavlopoulos, S., Dischinger, P., Graveel, C., Aguirre, A. J., Steensma, M., Haigis, K. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.026 · Cited by 89
Estimating Electron Density Support for Individual Atoms and Molecular Fragments in X-ray Structures
Meyder, A., Nittinger, E., Lange, G., Klein, R., & Rarey, M. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00391 · Cited by 86
Muraoka, S., Shima, F., Araki, M., Inoue, T., Yoshimoto, A., Ijiri, Y., Seki, N., Tamura, A., Kumasaka, T., Yamamoto, M., et al. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.04.058 · Cited by 81
Structures of N-terminally processed KRAS provide insight into the role of N-acetylation
Dharmaiah, S., Tran, T. H., Messing, S. A. J., Agamasu, C., Gillette, W., Yan, W., Waybright, T. J., Alexander, P., Esposito, D., Nissley, D. V., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-46846-w · Cited by 77
What does AlphaFold mean for drug discovery?
Mullard, A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00161-0 · Cited by 76
Drugging All RAS Isoforms With One Pocket
Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A., & McConnell, D. B. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0221 · Cited by 75
Kalbitzer, H. R., Rosnizeck, I. C., Munte, C. E., Narayanan, S. P., Kropf, V., & Spoerner, M. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201305741 · Cited by 68
ProtCID: a data resource for structural information on protein interactions
Xu, Q., & Dunbrack, R. L. (2020) · Nature Communications · doi:10.1038/s41467-020-14301-4 · Cited by 61
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 · doi:10.1002/ange.201201358 · Cited by 61
Béry, N., Cruz-Migoni, A., Bataille, C. J. R., Quevedo, C. E., Tulmin, H., Miller, A., Russell, A. J., Phillips, S. E. V., Carr, S. B., & Rabbitts, T. H. (2018) · eLife · doi:10.7554/elife.37122 · Cited by 56
KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation
Lu, J., Bera, A. K., Gondi, S. R., & Westover, K. D. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00974 · Cited by 51
Abbott, J. R., Hodges, T. R., Daniels, R. N., Patel, P. A., Kennedy, J. P., Howes, J. E., Akan, D. T., Burns, M. C., Sai, J., Sobolik, T., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00360 · Cited by 44
Kelow, S. P., Adolf‐Bryfogle, J., & Dunbrack, R. L. (2020) · mAbs · doi:10.1080/19420862.2020.1840005 · Cited by 44
RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site
Haza, K. Z., Martin, H. L., Rao, A., Turner, A. L., Saunders, S. E., Petersen, B., Tiede, C., Tipping, K. W., Tang, A. A.-S., Ajayi, M. O., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24316-0 · Cited by 42
Holzapfel, G. A., Buhrman, G., & Mattos, C. (2012) · Biochemistry · doi:10.1021/bi300509j · Cited by 35
Li, Y., Zhang, Y., Großerueschkamp, F., Stephan, S., Cui, Q., Kötting, C., Xia, F., & Gerwert, K. B. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.8b00342 · Cited by 35
Faezov, B., & Dunbrack, R. L. (2021) · PLoS ONE · doi:10.1371/journal.pone.0253411 · Cited by 35
Structural basis of the atypical activation mechanism of KRASV14I
Bera, A. K., Lu, J., Wales, T. E., Gondi, S. R., Gurbani, D., Nelson, A., Engen, J. R., & Westover, K. D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009131 · Cited by 31
Chen, F., Li, X., Zhu, H.-P., & Huang, W. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00280 · Cited by 30
FireDB: a compendium of biological and pharmacologically relevant ligands
Maietta, P., López, G., Carro, A., Pingilley, B. J., León, L., Valencia, A., & Tress, M. (2013) · Nucleic Acids Res. · doi:10.1093/nar/gkt1127 · Cited by 26
Comparative structural dynamic analysis of GTPases
Li, H., Yao, X., & Grant, B. J. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006364 · Cited by 19
Lee, K., Fang, Z., Enomoto, M., Gasmi-Seabrook, G. M. C., Zheng, L., Koide, S., Ikura, M., & Marshall, C. B. (2020) · Angewandte Chemie · doi:10.1002/ange.202001758 · Cited by 15
Colloc’h, N., Lopes, P. D. O., Spoerner, M., Dhaussy, A., Prangé, T., Kalbitzer, H. R., & Girard, É. (2022) · Acta Crystallographica Section A Foundations and Advances · doi:10.1107/s2053273322096334 · Cited by 2
Cited by
Still being checked.
Metadata
- Authors
- Parker, M. I., Meyer, J. E., Golemis, E. A., & Dunbrack
- Affiliations
- Fox Chase Cancer Center (US)
- Corresponding author
- Dunbrack,, Roland L.
- Published
- 2023-03-31
- OpenAlex
- W4361837267
- Cited by
- 0
- References
- 65
- Type
- other
- Language
- en
- Open access
- gold
- doi.org
- Funders
- National Institutes of Health (CA006927)
- National Cancer Institute (CA 006927, P30CA006927)
- National Institute of General Medical Sciences (R35GM122517)
- 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 Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras, KRAS, NRAS, HRAS, GTP-bound state, RAS mutations, G12D mutation, G12V mutation, RAS inhibitors, inhibitor binding mode
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
