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Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States.

Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD, Renslo AR, Burke JE, Shokat KM
Cell Chem Biol 24 1455-1466.e14 (2017)
Related entries: 5vbm, 5vbz

Cited: 50 times
EuropePMC logo PMID: 29033317

Abstract

Covalent inhibitors of K-Ras(G12C) have been reported that exclusively recognize the GDP state. Here, we utilize disulfide tethering of a non-natural cysteine (K-Ras(M72C)) to identify a new switch-II pocket (S-IIP) binding ligand (2C07) that engages the active GTP state. Co-crystal structures of 2C07 bound to H-Ras(M72C) reveal binding in a cryptic groove we term S-IIG. In the GppNHp state, 2C07 binding to a modified S-IIP pushes switch I away from the nucleotide, breaking the network of polar contacts essential for adopting the canonical GTP state. Biochemical studies show that 2C07 alters nucleotide preference and inhibits SOS binding and catalyzed nucleotide exchange. 2C07 was converted to irreversible covalent analogs, which target both nucleotide states, inhibit PI3K activation in vitro, and function as occupancy probes to detect reversible engagement in competition assays. Targeting both nucleotide states opens the possibility of inhibiting oncogenic mutants of Ras, which exist predominantly in the GTP state in cells.

Reviews - 5vbe mentioned but not cited (1)

  1. Pharmacological targeting of RAS: Recent success with direct inhibitors. O'Bryan JP. Pharmacol Res 139 503-511 (2019)

Articles - 5vbe mentioned but not cited (3)

  1. Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States. Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD, Renslo AR, Burke JE, Shokat KM. Cell Chem Biol 24 1455-1466.e14 (2017)
  2. Bifunctional Small-Molecule Ligands of K-Ras Induce Its Association with Immunophilin Proteins. Zhang Z, Shokat KM. Angew Chem Int Ed Engl 58 16314-16319 (2019)
  3. Organization of Farnesylated, Carboxymethylated KRAS4B on Membranes. Barklis E, Stephen AG, Staubus AO, Barklis RL, Alfadhli A. J Mol Biol 431 3706-3717 (2019)


Reviews citing this publication (27)

  1. RAS-targeted therapies: is the undruggable drugged? Moore AR, Rosenberg SC, McCormick F, Malek S. Nat Rev Drug Discov 19 533-552 (2020)
  2. Therapeutic strategies to target RAS-mutant cancers. Ryan MB, Corcoran RB. Nat Rev Clin Oncol 15 709-720 (2018)
  3. KRAS mutation: from undruggable to druggable in cancer. Huang L, Guo Z, Wang F, Fu L. Signal Transduct Target Ther 6 386 (2021)
  4. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. Cancer Treat Rev 84 101974 (2020)
  5. Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers. Nussinov R, Jang H, Tsai CJ, Cheng F. PLoS Comput Biol 15 e1006658 (2019)
  6. Therapeutic targeting of RAS: New hope for drugging the "undruggable". Khan I, Rhett JM, O'Bryan JP. Biochim Biophys Acta Mol Cell Res 1867 118570 (2020)
  7. Emerging strategies to target RAS signaling in human cancer therapy. Chen K, Zhang Y, Qian L, Wang P. J Hematol Oncol 14 116 (2021)
  8. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Zhu G, Pei L, Xia H, Tang Q, Bi F. Mol Cancer 20 143 (2021)
  9. Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations. König D, Savic Prince S, Rothschild SI. Cancers (Basel) 13 804 (2021)
  10. Personal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health. Cheng F, Liang H, Butte AJ, Eng C, Nussinov R. Pharmacol Rev 71 1-19 (2019)
  11. The path to the clinic: a comprehensive review on direct KRASG12C inhibitors. Kwan AK, Piazza GA, Keeton AB, Leite CA. J Exp Clin Cancer Res 41 27 (2022)
  12. Targeting KRAS mutant cancers: from druggable therapy to drug resistance. Zhu C, Guan X, Zhang X, Luan X, Song Z, Cheng X, Zhang W, Qin JJ. Mol Cancer 21 159 (2022)
  13. The Ins and Outs of RAS Effector Complexes. Kiel C, Matallanas D, Kolch W. Biomolecules 11 236 (2021)
  14. Inhibition of Nonfunctional Ras. Nussinov R, Jang H, Gursoy A, Keskin O, Gaponenko V. Cell Chem Biol 28 121-133 (2021)
  15. Mechanism of activation and the rewired network: New drug design concepts. Nussinov R, Zhang M, Maloney R, Tsai CJ, Yavuz BR, Tuncbag N, Jang H. Med Res Rev 42 770-799 (2022)
  16. Biology, pathology, and therapeutic targeting of RAS. Rhett JM, Khan I, O'Bryan JP. Adv Cancer Res 148 69-146 (2020)
  17. Computational Structural Biology: Successes, Future Directions, and Challenges. Nussinov R, Tsai CJ, Shehu A, Jang H. Molecules 24 E637 (2019)
  18. KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered? Bannoura SF, Khan HY, Azmi AS. Front Oncol 12 1013902 (2022)
  19. The Research Progress of Direct KRAS G12C Mutation Inhibitors. Yang A, Li M, Fang M. Pathol Oncol Res 27 631095 (2021)
  20. KRAS oncogene may be another target conquered in non-small cell lung cancer (NSCLC). Chen H, Zhao J. Thorac Cancer 11 3425-3435 (2020)
  21. Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives. Tisi R, Gaponenko V, Vanoni M, Sacco E. Biomolecules 10 E1535 (2020)
  22. Dynamic structural biology at the protein membrane interface. Burke JE. J Biol Chem 294 3872-3880 (2019)
  23. Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives. Li JX, Li RZ, Ma LR, Wang P, Xu DH, Huang J, Li LQ, Tang L, Xie Y, Leung EL, Yan PY. Front Pharmacol 13 875330 (2022)
  24. KRAS: A Druggable Target in Colon Cancer Patients. Negri F, Bottarelli L, de'Angelis GL, Gnetti L. Int J Mol Sci 23 4120 (2022)
  25. Targeting KRAS in Pancreatic Cancer. Cowzer D, Zameer M, Conroy M, Kolch W, Duffy AG. J Pers Med 12 1870 (2022)
  26. Targeting Ras with protein engineering. Tomazini A, Shifman JM. Oncotarget 14 672-687 (2023)
  27. Therapeutic developments in pancreatic cancer. Hu ZI, O'Reilly EM. Nat Rev Gastroenterol Hepatol (2023)

Articles citing this publication (19)

  1. Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes. Ramrath DJF, Niemann M, Leibundgut M, Bieri P, Prange C, Horn EK, Leitner A, Boehringer D, Schneider A, Ban N. Science 362 eaau7735 (2018)
  2. GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf. Zhang Z, Gao R, Hu Q, Peacock H, Peacock DM, Dai S, Shokat KM, Suga H. ACS Cent Sci 6 1753-1761 (2020)
  3. Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D. Johnson CW, Lin YJ, Reid D, Parker J, Pavlopoulos S, Dischinger P, Graveel C, Aguirre AJ, Steensma M, Haigis KM, Mattos C. Cell Rep 28 1538-1550.e7 (2019)
  4. BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions. Bery N, Cruz-Migoni A, Bataille CJ, Quevedo CE, Tulmin H, Miller A, Russell A, Phillips SE, Carr SB, Rabbitts TH. Elife 7 e37122 (2018)
  5. KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge. Mao Z, Xiao H, Shen P, Yang Y, Xue J, Yang Y, Shang Y, Zhang L, Li X, Zhang Y, Du Y, Chen CC, Guo RT, Zhang Y. Cell Discov 8 5 (2022)
  6. Structural basis of the atypical activation mechanism of KRASV14I. Bera AK, Lu J, Wales TE, Gondi S, Gurbani D, Nelson A, Engen JR, Westover KD. J Biol Chem 294 13964-13972 (2019)
  7. Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins. Zhang Y, Wang Z, Ma X, Yang S, Hu X, Tao J, Hou Y, Bai G. Acta Pharm Sin B 9 294-303 (2019)
  8. RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site. Haza KZ, Martin HL, Rao A, Turner AL, Saunders SE, Petersen B, Tiede C, Tipping K, Tang AA, Ajayi M, Taylor T, Harvey M, Fishwick KM, Adams TL, Gaule TG, Trinh CH, Johnson M, Breeze AL, Edwards TA, McPherson MJ, Tomlinson DC. Nat Commun 12 4045 (2021)
  9. Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations. Yu Z, Su H, Chen J, Hu G. Molecules 27 5596 (2022)
  10. Biochemical characterization of the interaction between KRAS and Argonaute 2. Waninger JJ, Beyett TS, Gadkari VV, Siebenaler RF, Kenum C, Shankar S, Ruotolo BT, Chinnaiyan AM, Tesmer JJG. Biochem Biophys Rep 29 101191 (2022)
  11. Chemical Proteomic Characterization of a Covalent KRASG12C Inhibitor. Wijeratne A, Xiao J, Reutter C, Furness KW, Leon R, Zia-Ebrahimi M, Cavitt RN, Strelow JM, Van Horn RD, Peng SB, Barda DA, Engler TA, Chalmers MJ. ACS Med Chem Lett 9 557-562 (2018)
  12. Conformation-locking antibodies for the discovery and characterization of KRAS inhibitors. Davies CW, Oh AJ, Mroue R, Steffek M, Bruning JM, Xiao Y, Feng S, Jayakar S, Chan E, Arumugam V, Uribe SC, Drummond J, Frommlet A, Lu C, Franke Y, Merchant M, Koeppen H, Quinn JG, Malhotra S, Do S, Gazzard L, Purkey HE, Rudolph J, Mulvihill MM, Koerber JT, Wang W, Evangelista M. Nat Biotechnol 40 769-778 (2022)
  13. Engineered variants of the Ras effector protein RASSF5 (NORE1A) promote anticancer activities in lung adenocarcinoma. Singh A, Erijman A, Noronha A, Kumar H, Peleg Y, Yarden Y, Shifman JM. J Biol Chem 297 101353 (2021)
  14. The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells. Tisi R, Spinelli M, Palmioli A, Airoldi C, Cazzaniga P, Besozzi D, Nobile MS, Mazzoleni E, Arnhold S, De Gioia L, Grandori R, Peri F, Vanoni M, Sacco E. Front Mol Biosci 8 625979 (2021)
  15. Delineating the RAS Conformational Landscape. Parker MI, Meyer JE, Golemis EA, Dunbrack RL. Cancer Res 82 2485-2498 (2022)
  16. 143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models. Xu LS, Zheng SX, Mei LH, Yang KX, Wang YF, Zhou Q, Kong XT, Zheng MY, Jiang HL, Xie CY. Acta Pharmacol Sin 44 1475-1486 (2023)
  17. Beyond structural bioinformatics for genomics with dynamics characterization of an expanded KRAS mutational landscape. Ratnasinghe BD, Haque N, Wagenknecht JB, Jensen DR, Valdivia Esparza GK, Leverence EN, Milech De Assuncao T, Mathison AJ, Lomberk G, Smith BC, Volkman BF, Urrutia R, Zimmermann MT. Comput Struct Biotechnol J 21 4790-4803 (2023)
  18. Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations. Shi S, Zheng L, Ren Y, Wang Z. Molecules 28 2886 (2023)
  19. Probing the KRas Switch II Groove by Fluorine NMR Spectroscopy. Peacock DM, Kelly MJS, Shokat KM. ACS Chem Biol 17 2710-2715 (2022)


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