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Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1.

van Haren MJ, Marechal N, Troffer-Charlier N, Cianciulli A, Sbardella G, Cavarelli J, Martin NI
Proc Natl Acad Sci U S A 114 3625-3630 (2017)
Related entries: 5lgq, 5lgr, 5lgs

Cited: 17 times
EuropePMC logo PMID: 28330993

Abstract

Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics. These constructs were found to be potent CARM1 inhibitors and also formed stable complexes with the enzyme. High-resolution crystal structures of CARM1 in complex with these compounds confirm a mode of binding that is indeed reflective of the transition state at the CARM1 active site. Given the transient nature of PRMT-substrate complexes, such transition state mimics represent valuable chemical tools for structural studies aimed at deciphering the regulation of arginine methylation mediated by the family of arginine methyltransferases.

Articles - 5lgp mentioned but not cited (1)

  1. Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1. van Haren MJ, Marechal N, Troffer-Charlier N, Cianciulli A, Sbardella G, Cavarelli J, Martin NI. Proc Natl Acad Sci U S A 114 3625-3630 (2017)


Reviews citing this publication (2)

  1. Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies. Sauter C, Simonet J, Guidez F, Dumétier B, Pernon B, Callanan M, Bastie JN, Aucagne R, Delva L. Cancers (Basel) 14 5443 (2022)
  2. Chemical probes and methods for the study of protein arginine methylation. Brown T, Nguyen T, Zhou B, Zheng YG. RSC Chem Biol 4 647-669 (2023)

Articles citing this publication (14)

  1. Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity. Gao Y, van Haren MJ, Moret EE, Rood JJM, Sartini D, Salvucci A, Emanuelli M, Craveur P, Babault N, Jin J, Martin NI. J Med Chem 62 6597-6614 (2019)
  2. CARM1 methylates MED12 to regulate its RNA-binding ability. Cheng D, Vemulapalli V, Lu Y, Shen J, Aoyagi S, Fry CJ, Yang Y, Foulds CE, Stossi F, Treviño LS, Mancini MA, O'Malley BW, Walker CL, Boyer TG, Bedford MT. Life Sci Alliance 1 e201800117 (2018)
  3. Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics. Gao Y, van Haren MJ, Buijs N, Innocenti P, Zhang Y, Sartini D, Campagna R, Emanuelli M, Parsons RB, Jespers W, Gutiérrez-de-Terán H, van Westen GJP, Martin NI. J Med Chem 64 12938-12963 (2021)
  4. Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues. Chen D, Dong C, Dong G, Srinivasan K, Min J, Noinaj N, Huang R. J Med Chem 63 8419-8431 (2020)
  5. Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors. Halby L, Marechal N, Pechalrieu D, Cura V, Franchini DM, Faux C, Alby F, Troffer-Charlier N, Kudithipudi S, Jeltsch A, Aouadi W, Decroly E, Guillemot JC, Page P, Ferroud C, Bonnefond L, Guianvarc'h D, Cavarelli J, Arimondo PB. Philos Trans R Soc Lond B Biol Sci 373 20170072 (2018)
  6. A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes. Iyamu ID, Al-Hamashi AA, Huang R. Biomolecules 11 854 (2021)
  7. Discovery of a potent and dual-selective bisubstrate inhibitor for protein arginine methyltransferase 4/5. Al-Hamashi AA, Chen D, Deng Y, Dong G, Huang R. Acta Pharm Sin B 11 2709-2718 (2021)
  8. Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase. Iyamu ID, Vilseck JZ, Yadav R, Noinaj N, Huang R. Angew Chem Int Ed Engl 61 e202114813 (2022)
  9. Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach. Iannelli G, Milite C, Marechal N, Cura V, Bonnefond L, Troffer-Charlier N, Feoli A, Rescigno D, Wang Y, Cipriano A, Viviano M, Bedford MT, Cavarelli J, Castellano S, Sbardella G. J Med Chem 65 11574-11606 (2022)
  10. Structural Studies Provide New Insights into the Role of Lysine Acetylation on Substrate Recognition by CARM1 and Inform the Design of Potent Peptidomimetic Inhibitors. Zhang Y, Marechal N, van Haren MJ, Troffer-Charlier N, Cura V, Cavarelli J, Martin NI. Chembiochem 22 3469-3476 (2021)
  11. Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4). Gunnell EA, Al-Noori A, Muhsen U, Davies CC, Dowden J, Dreveny I. Biochem J 477 787-800 (2020)
  12. A Direct Assay for Measuring the Activity and Inhibition of Coactivator-Associated Arginine Methyltransferase 1. Zhang Y, van Haren MJ, Marechal N, Troffer-Charlier N, Cura V, Cavarelli J, Martin NI. Biochemistry (2022)
  13. Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor. Feoli A, Iannelli G, Cipriano A, Milite C, Shen L, Wang Z, Hadjikyriacou A, Lowe TL, Safaeipour C, Viviano M, Sarno G, Morretta E, Monti MC, Yang Y, Clarke SG, Cosconati S, Castellano S, Sbardella G. J Med Chem 66 13665-13683 (2023)
  14. Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity. Wang S, Klein SO, Urban S, Staudt M, Barthes NPF, Willmann D, Bacher J, Sum M, Bauer H, Peng L, Rennar GA, Gratzke C, Schüle KM, Zhang L, Einsle O, Greschik H, MacLeod C, Thomson CG, Jung M, Metzger E, Schüle R. Nat Commun 15 43 (2024)


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