Structural basis for the action of the drug trametinib at KSR-bound MEK
Open accessAbstract
The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology 1, and more recently in immunotherapy 2,3 and ageing 4. However, many MEK inhibitors are limited owing to on-target toxicities 5-7 and drug resistance 8-10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.
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Trametinib glues MEK to KSR.
“In 2020, structural studies with trametinib, unlike other MEK inhibitors revealed that it glues MEK to KSR (Fig. 3C and 6).106”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [106]
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Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Towards automated crystallographic structure refinement with <i>phenix.refine</i>
Afonine, P. V., Grosse-Kunstleve, R. W., Echols, N., Headd, J. J., Moriarty, N. W., Mustyakimov, M., Terwilliger, T. C., Urzhumtsev, A., Zwart, P. H., & Adams, P. D. (2012) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444912001308 · Cited by 5,511 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
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 · see citing works
Long, G. V., Stroyakovskiy, D., Gogas, H. J., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Grob, J., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60898-4 · Cited by 1,397 · see citing works
Moriarty, N. W., Grosse‐Kunstleve, R. W., & Adams, P. D. (2009) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909029436 · Cited by 1,347 · see citing works
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
The drug–target residence time model: a 10-year retrospective
Copeland, R. A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.18 · Cited by 726 · see citing works
Ebert, P. J. R., Cheung, J., Yang, Y., McNamara, E., Hong, R., Moskalenko, M., Gould, S. E., Maecker, H., Irving, B. A., Kim, J. M., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.024 · Cited by 713 · see citing works
Regulation of RAF protein kinases in ERK signalling
Lavoie, H., & Therrien, M. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3979 · Cited by 683 · see citing works
MEK1 mutations confer resistance to MEK and B-RAF inhibition
Emery, C. M., Vijayendran, K. G., Zipser, M. C., Sawyer, A. M., Niu, L., Kim, J. J., Hatton, C., Chopra, R., Oberholzer, P. A., Karpova, M. B., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905833106 · Cited by 642 · see citing works
Ohren, J. F., Chen, H., Pavlovsky, A. G., Whitehead, C. E., Zhang, E., Kuffa, P., Yan, C., McConnell, P., Spessard, C., Banotai, C. A., et al. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb859 · Cited by 635 · see citing works
Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0367-9 · Cited by 634 · see citing works
Gilmartin, A. G., Bleam, M. R., Groy, A., Moss, K. G., Minthorn, E. A., Kulkarni, S. G., Rominger, C. M., Erskine, S. G., Fisher, K. E., Yang, J., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2200 · Cited by 590 · see citing works
A dimerization-dependent mechanism drives RAF catalytic activation
Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. (2009) · Nature · doi:10.1038/nature08314 · Cited by 490 · see citing works
Targeting Alterations in the RAF–MEK Pathway
Yaeger, R. D., & Corcoran, R. B. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1321 · Cited by 477 · see citing works
Liu, L., Mayes, P. A., Eastman, S., Shi, H., Yadavilli, S., Zhang, T., Yang, J., Seestaller-Wehr, L., Zhang, S.-Y., Hopson, C., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2339 · Cited by 446 · see citing works
The clinical development of MEK inhibitors
Zhao, Y., & Adjei, A. A. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.83 · Cited by 403 · see citing works
Lito, P., Saborowski, A., Yue, J., Solomon, M., Joseph, E., Gadal, S., Saborowski, M., Kastenhuber, E., Fellmann, C., Ohara, K., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.011 · Cited by 324 · see citing works
Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
Hatzivassiliou, G., Haling, J. R., Chen, H., Song, K. W., Price, S., Heald, R. A., Hewitt, J. F. M., Zak, M., Peck, A., Orr, C., et al. (2013) · Nature · doi:10.1038/nature12441 · Cited by 317 · see citing works
The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans
Kornfeld, K., Hom, D. B., & Horvitz, H. R. (1995) · Cell · doi:10.1016/0092-8674(95)90206-6 · Cited by 299 · see citing works
Long‐lasting target binding and rebinding as mechanisms to prolongin vivodrug action
Vauquelin, G., & Charlton, S. J. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00936.x · Cited by 298 · see citing works
Vasta, J. D., Corona, C. R., Wilkinson, J., Zimprich, C., Hartnett, J. R., Ingold, M. R., Zimmerman, K., Machleidt, T., Kirkland, T. A., Huwiler, K. G., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.10.010 · Cited by 285 · see citing works
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK
Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., & Barford, D. (2011) · Nature · doi:10.1038/nature09860 · Cited by 254 · see citing works
Self-citationLoRusso, P. M., Krishnamurthi, S., Rinehart, J. J., Nabell, L. M., Malburg, L., Chapman, P. B., DePrimo, S. E., Bentivegna, S., Wilner, K. D., Tan, W., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1883 · Cited by 253 · see citing works
Haling, J. R., Sudhamsu, J., Yen, I., Sideris, S., Sandoval, W. N., Phung, W., Bravo, B. J., Giannetti, A. M., Peck, A., Masselot, A., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.07.007 · Cited by 242 · see citing works
The Ras-Erk-ETS-signaling pathway is a drug target for longevity
Slack, C., Alic, N., Foley, A., Cabecinha, M., Hoddinott, M. P., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.06.023 · Cited by 224 · see citing works
Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors
Fischmann, T. O., Smith, C. K., Mayhood, T., Myers, J. E., Reichert, P., Mannarino, A., Carr, D. M., Zhu, H. Y. H., Wong, J. K. Y., Yang, R., et al. (2009) · Biochemistry · doi:10.1021/bi801898e · Cited by 187 · see citing works
Ishii, N., Harada, N., Joseph, E. W., Ohara, K., Miura, T., Sakamoto, H., Matsuda, Y., Tomii, Y., Tachibana-Kondo, Y., Iikura, H., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3937 · Cited by 179 · see citing works
Ribas, A., Butler, M. O., Lutzky, J., Lawrence, D. P., Robert, C., Miller, W. H., Linette, G. P., Ascierto, P. A., Kuzel, T. M., Algazi, A. P., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.3003 · Cited by 158 · see citing works
MEK drives BRAF activation through allosteric control of KSR proteins
Lavoie, H., Sahmi, M., Maisonneuve, P., Marullo, S. A., Thevakumaran, N., Jin, T., Kurinov, I. V., Sicheri, F., & Therrien, M. (2018) · Nature · doi:10.1038/nature25478 · Cited by 153 · see citing works
Prospects for pharmacological targeting of pseudokinases
Kung, J. E., & Jura, N. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0018-3 · Cited by 141 · see citing works
Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.
Infante, J. R., Fecher, L. A., Nallapareddy, S., Gordon, M. S., Flaherty, K. T., Cox, D. S., DeMarini, D. J., Morris, S. R., Burris, H. A., & Messersmith, W. A. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.2503 · Cited by 121 · see citing works
Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization
Liau, N. P. D., Wendorff, T. J., Quinn, J. G., Steffek, M., Phung, W., Liu, P., Tang, J., Irudayanathan, F. J., Izadi, S., Shaw, A. S., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0365-0 · Cited by 96 · see citing works
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling
Dhawan, N. S., Scopton, A. P., & Dar, A. C. (2016) · Nature · doi:10.1038/nature19327 · Cited by 94 · see citing works
Self-citationStrub, T., Ghiraldini, F. G., Carcamo, S., Li, M., Wroblewska, A., Singh, R., Goldberg, M. S., Hasson, D., Wang, Z., Gallagher, S. J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05966-z · Cited by 93 · see citing works
Huang, W., Yang, A. H., Matsumoto, D., Collette, W., Marroquin, L. D., Ko, M., Aguirre, S. A., & Younis, H. S. (2009) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2009.0060 · Cited by 90 · see citing works
How Structural Biologists and the Protein Data Bank Contributed to Recent FDA New Drug Approvals
Westbrook, J., & Burley, S. K. (2018) · Structure · doi:10.1016/j.str.2018.11.007 · Cited by 88 · see citing works
Viswanatha, R., Li, Z., Hu, Y., & Perrimon, N. (2018) · eLife · doi:10.7554/elife.36333 · Cited by 79 · see citing works
Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
Sos, M. L., Levin, R. S., Gordan, J. D., Osés-Prieto, J. A., Webber, J. T., Salt, M. B., Hann, B. C., Burlingame, A. L., McCormick, F. P., Bandyopadhyay, S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.010 · Cited by 73 · see citing works
Yoshida, T., Kakegawa, J., Yamaguchi, T., Hantani, Y., Okajima, N., Sakai, T., Watanabe, Y., & Nakamura, M. (2012) · Oncotarget · doi:10.18632/oncotarget.747 · Cited by 62 · see citing works
Identification of JTP‐70902, a p15INK4b‐inductive compound, as a novel MEK1/2 inhibitor
Yamaguchi, T., Yoshida, T., Kurachi, R., Kakegawa, J., Hori, Y., Nanayama, T., Hayakawa, K., Abe, H., Takagi, K., Matsuzaki, Y., et al. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00604.x · Cited by 54 · see citing works
Quantitative, Real-Time Measurements of Intracellular Target Engagement Using Energy Transfer
Robers, M. B., Vasta, J. D., Corona, C. R., Ohana, R. F., Hurst, R., Jhala, M. A., Comess, K. M., & Wood, K. V. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8891-4_3 · Cited by 48 · see citing works
V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer
Gao, Y., Maria, A., Na, N., Paula, A. D. C., Gorelick, A. N., Hechtman, J. F., Carson, J., Lefkowitz, R. A., Weigelt, B., Taylor, B. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0356 · Cited by 42 · see citing works
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Chasing molecular glue degraders: screening approaches
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- Authors
- Khan, Z. M., Real, A. M., Marsiglia, W. M., Chow, A., Duffy, M. E., Yerabolu, J. R., Scopton, A. P., & Dar, A. C.
- Affiliations
- Tisch Cancer Institute (US)
- Corresponding author
- Dar, Arvin C.
- Venue
- Nature
- Published
- 2020-09-14
- Volume
- 588
- Issue
- 7838
- Pages
- 509-514
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7746607
- OpenAlex
- W3085029011
- Cited by
- 178
- References
- 46
- Citations by year
- 2026: 28 · 2025: 40 · 2024: 27 · 2023: 31 · 2022: 26 · 2021: 25 · 2020: 1
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (U54OD020353)
- National Cancer Institute (F30CA232454, F99CA212474, DP2CA186570, T32CA078207, K00CA212474, R01CA227636, P30CA196521)
- National Institute of General Medical Sciences (T32GM062754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- 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
- Keywords
- MEK, trametinib, KSR, MEK inhibitors, allosteric binding pocket, drug resistance, drug residence time, Ras signaling, ERK signaling, protein-protein interfaces
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Humans, Models, Molecular, Protein Binding, Protein Kinases, Pyridones, Pyrimidinones, Substrate Specificity, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors, raf Kinases, Mice
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