Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Protein methyltransferases as a target class for drug discovery

Nature Reviews Drug Discovery volume 8, pages 724–732 (2009)Cite this article

Key Points

  • Post-translational modifications of histones, the major protein components of chromatin, provide the mechanistic underpinning for epigenetic regulation of gene transcription. Among the enzymes that modify histones, the protein methyltransferases (PMTs) are particularly attractive as drug targets.

  • A number of PMTs have been directly associated with the pathogenesis of diseases such as human cancers, inflammatory diseases, metabolic diseases, neurodegenerative diseases and other unmet medical needs of patients.

  • The PMT target class is composed of two enzyme families: the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). All of the PMTs use a common, small-molecule cofactor, S-adenosyl-L-methionine (SAM), as the universal methyl donor for the enzymatic methylation of protein lysine and arginine side chains.

  • The universal use of SAM by PMTs is reminiscent of the universal use of ATP by protein kinases, a well-established drug target class of enzymes. As for the ATP-binding pockets of kinases, the SAM-binding pockets of PMTs show substantial structural diversity in terms of both the amino acids that line the enzyme pockets and the conformation of ligands bound in the pockets of various PMTs, as revealed by X-ray crystallographic studies. These results suggest that the development of selective inhibitors of specific PMTs is achievable.

  • Here, we review the biological, biochemical, medicinal chemical and structural biological data that together present the PMTs as a large, pathology-relevant, druggable target class for drug discovery. As for the ATP-binding pocket of kinases, we suggest that the SAM-binding pockets of PMTs provide a clear target for pharmacological modulation of selective PMT activity.

Abstract

The protein methyltransferases (PMTs) — which methylate protein lysine and arginine residues and have crucial roles in gene transcription — are emerging as an important group of enzymes that play key parts in normal physiology and human diseases. The collection of human PMTs is a large and diverse group of enzymes that have a common mechanism of catalysis. Here, we review the biological, biochemical and structural data that together present PMTs as a novel, chemically tractable target class for drug discovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A nucleosome and the post-translational histone protein modifications that can influence epigenetic regulation of gene transcription.
Figure 2: PMT-catalysed methylation of proteins by an SN2 reaction with SAM as the methyl donor.
Figure 3: Variations in the configuration of SAM or SAH bound within the active sites of different PMTs.

Similar content being viewed by others

References

  1. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  Google Scholar 

  2. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007). A thorough overview of post-translational modifications on core histones, the enzymes that mediate these modifications and the biological functions of the modification.

    Article  CAS  Google Scholar 

  3. Smith, B. C. & Denu, J. M. Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta 1789, 45–57 (2008). An excellent review of the chemical biology of lysine- and arginine-modifying enzymes.

    Article  Google Scholar 

  4. Cole, P. A. Chemical probes for histone-modifying enzymes. Nature Chem. Biol. 4, 590–597 (2008).

    Article  CAS  Google Scholar 

  5. Keppler, B. R. & Archer, T. K. Chromatin-modifying enzymes as therapeutic targets — Part 1. Expert Opin. Ther. Targets. 12, 1301–1312 (2008).

    Article  CAS  Google Scholar 

  6. Pray, L. At the flick of a switch: epigenetic drugs. Chem. Biol. 15, 640–641 (2008).

    Article  CAS  Google Scholar 

  7. Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    Article  CAS  Google Scholar 

  8. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  Google Scholar 

  9. Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8, 355–367 (2007).

    Article  CAS  Google Scholar 

  10. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).

    Article  CAS  Google Scholar 

  11. Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14, 355–368 (2008).

    Article  CAS  Google Scholar 

  12. Jansson, M. et al. Arginine methylation regulates the p53 response. Nature Cell Biol. 10, 1431–1439 (2008).

    Article  CAS  Google Scholar 

  13. Hong, H. et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer 101, 83–89 (2004).

    Article  CAS  Google Scholar 

  14. Schneider, R., Bannister, A. J. & Kouzarides, T. Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem. Sci. 27, 396–402 (2002).

    Article  CAS  Google Scholar 

  15. Simon, J. A. & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).

    Article  CAS  Google Scholar 

  16. Dillon, S. C., Zhang, X., Trievel, R. C. & Cheng, X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6, 227 (2005).

    Article  Google Scholar 

  17. Ryu, H. et al. ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Proc. Natl Acad. Sci. USA 103, 19176–19181 (2006).

    Article  CAS  Google Scholar 

  18. Cheng, D., Cote, J., Shaaban, S. & Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 25, 71–83 (2007).

    Article  Google Scholar 

  19. Li, Y. et al. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes. Relevance to diabetes and inflammation. J. Biol. Chem. 283, 26771–26781 (2008).

    Article  CAS  Google Scholar 

  20. Covic, M. et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-κB-dependent gene expression. EMBO J. 24, 85–96 (2005).

    Article  CAS  Google Scholar 

  21. Hassa, P. O., Covic, M., Bedford, M. T. & Hottiger, M. O. Protein arginine methyltransferase 1 coactivates NF-κB-dependent gene expression synergistically with CARM1 and PARP1. J. Mol. Biol. 377, 668–678 (2008).

    Article  CAS  Google Scholar 

  22. Huang, J. et al. Trimethylation of histone H3 lysine 4 by Set1 in the lytic infection of human herpes simplex virus 1. J. Virol. 80, 5740–5746 (2006).

    Article  CAS  Google Scholar 

  23. Jeong, S. J. et al. Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J. Virol. 80, 10036–10044 (2006).

    Article  CAS  Google Scholar 

  24. Cheng, X., Collins, R. E. & Zhang, X. Structural and sequence motifs of protein (histone) methylation enzymes. Annu. Rev. Biophys. Biomol. Struct. 34, 267–294 (2005).

    Article  CAS  Google Scholar 

  25. Goldstein, D. M., Gray, N. S. & Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery. Nature Rev. Drug Discov. 7, 391–397 (2008).

    Article  CAS  Google Scholar 

  26. Mook, R. A. The importance and complexity of target class selectivity in drug discovery. The American Association for Cancer Research Education Book 223–226 (The American Association for Cancer Research, Philadelphia, 2005).

    Google Scholar 

  27. Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, Hoboken, 2005).

    Google Scholar 

  28. Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892–23899 (2004).

    Article  CAS  Google Scholar 

  29. Allis, C. D. et al. New nomenclature for chromatin-modifying enzymes. Cell 131, 633–636 (2007).

    Article  CAS  Google Scholar 

  30. Zhang, X. & Bruice, T. C. Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases. Proc. Natl Acad. Sci. USA 105, 5728–5732 (2008). This work provides a detailed theoretical basis to explain the substrate specificity of the protein lysine methyltransferases.

    Article  CAS  Google Scholar 

  31. Fedorov, O. et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl Acad. Sci. USA 104, 20523–20528 (2007).

    Article  CAS  Google Scholar 

  32. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127–132 (2008).

    Article  CAS  Google Scholar 

  33. Min, J., Feng, Q., Li, Z., Zhang, Y. & Xu, R. M. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711–723 (2003).

    Article  CAS  Google Scholar 

  34. Sawada, K. et al. Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. J. Biol. Chem. 279, 43296–43306 (2004).

    Article  CAS  Google Scholar 

  35. Copeland, R. A. Enzymes: A Practical Introduction to Structure, Mechanism and Data Analysis 2nd edn (Wiley, Hoboken, 2000).

    Book  Google Scholar 

  36. Couture, J. F., Hauk, G., Thompson, M. J., Blackburn, G. M. & Trievel, R. C. Catalytic roles for carbon–oxygen hydrogen bonding in SET domain lysine methyltransferases. J. Biochem. 281, 19280–19287 (2006).

    CAS  Google Scholar 

  37. Collins, R. E. et al. In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J. Biol. Chem. 280, 5563–5570 (2005). This study provides a structural basis for the wide range of lysine methylation patterns that is achieved by different SET domain PKMTs.

    Article  CAS  Google Scholar 

  38. Trievel, R. C., Flynn, E. M., Houtz, R. L. & Hurley, J. H. Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT. Nature Struct. Biol. 10, 545–552 (2003).

    Article  CAS  Google Scholar 

  39. Zhang, X. et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 12, 177–185 (2003).

    Article  Google Scholar 

  40. Frederiks, F. et al. Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nature Struct. Mol. Biol. 15, 550–557 (2008).

    Article  CAS  Google Scholar 

  41. Chiang, P. K. Biological effects of inhibitors of S-adenosylhomocysteine hydrolase. Pharmacol. Ther. 77, 115–134 (1998).

    Article  CAS  Google Scholar 

  42. Bender, C. M., Zingg, J.-M. & Jones, P. A. DNA methylation as a target for drug design. Pharm. Res. 15, 175–187 (1998).

    Article  CAS  Google Scholar 

  43. Fiskus, W. et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol. Ther. 8, 939–950 (2009).

    Article  CAS  Google Scholar 

  44. Chang, Y. et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Struct. Mol. Biol. 16, 312–317 (2009).

    Article  CAS  Google Scholar 

  45. Allan, M. et al. N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 1218–1223 (2009). The first examples of potent, drug-like inhibitors of a human PMT.

    Article  CAS  Google Scholar 

  46. Purandare, A. V. et al. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 18, 4438–4441 (2008).

    Article  CAS  Google Scholar 

  47. Huynh, T. et al. Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 2924–2927 (2009).

    Article  CAS  Google Scholar 

  48. Copeland, R. A., Gontarek, R. & Luo, L. in Textbook of Drug Design and Discovery 4th edn Ch. 12 (eds. Krogsgaard-Larsen, P., Madsen, U. & Stromgaard, K.) 378–407 (Taylor and Francis, New York, 2009).

    Google Scholar 

  49. Troffer-Charlier, N., Cura, V., Hassenboehler, P., Moras, D. & Cavarelli, J. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains. EMBO J. 26, 4391–4401 (2007).

    Article  CAS  Google Scholar 

  50. Couture, J.-F., Collazo, E., Brunzelle, J. S. & Trievel, R. C. Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455–1465 (2005).

    Article  CAS  Google Scholar 

  51. Ma, W. W. & Adjei, A. A. Novel agents on the horizon for cancer therapy. CA Cancer J. Clin. 59, 111–137 (2009). A review of the current knowledge on how aberrant epigenetic mechanisms can contribute to the development of cancer and the progress in developing therapies that target these mechanisms.

    Article  Google Scholar 

  52. Cortez, C. C. & Jones, P. A. Chromatin, cancer and drug therapies. Mutat. Res. 647, 44–51 (2008).

    Article  CAS  Google Scholar 

  53. Kang, M. Y. et al. Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. Int. J. Cancer 121, 2192–2197 (2007).

    Article  CAS  Google Scholar 

  54. Watanabe, H. et al. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int. 8, 15 (2008).

    Article  Google Scholar 

  55. Kondo, Y. et al. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One 3, e2037 (2008).

    Article  Google Scholar 

  56. Tkachuk, D., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992).

    Article  CAS  Google Scholar 

  57. Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992).

    Article  CAS  Google Scholar 

  58. Liedtke, M. & Cleary, M. L. Therapeutic targeting of MLL. Blood 113, 6061–6068 (2009).

    Article  CAS  Google Scholar 

  59. Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biol. 9, 804–812 (2007).

    Article  CAS  Google Scholar 

  60. Marango, J. et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111, 3145–3154 (2008).

    Article  CAS  Google Scholar 

  61. Kim, J. Y. et al. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol. Cell Biol. 28, 2023–2034 (2008).

    Article  CAS  Google Scholar 

  62. Lauring, J. et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 111, 856–864 (2008).

    Article  CAS  Google Scholar 

  63. Angrand, P. O. et al. NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74, 79–88 (2001).

    Article  CAS  Google Scholar 

  64. Rosati, R. et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99, 3857–3860 (2002).

    Article  CAS  Google Scholar 

  65. Tonon, G. et al. High-resolution genomic profiles of human lung cancer. Proc. Natl Acad. Sci. USA 102, 9625–9630 (2005).

    Article  CAS  Google Scholar 

  66. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).

    Article  CAS  Google Scholar 

  67. Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).

    Article  CAS  Google Scholar 

  68. Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biol. 6, 731–740 (2004).

    Article  CAS  Google Scholar 

  69. Hamamoto, R. et al. Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer Sci. 97, 113–118 (2006).

    Article  CAS  Google Scholar 

  70. Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).

    Article  CAS  Google Scholar 

  71. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  Google Scholar 

  72. Subramanian, K. et al. Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol. Cell 30, 336–347 (2008).

    Article  CAS  Google Scholar 

  73. Nishikawa, N. et al. Gene amplification and overexpression of PRDM14 in breast cancers. Cancer Res. 67, 9649–9657 (2007).

    Article  CAS  Google Scholar 

  74. Majumder, S., Liu, Y., Ford, O. H., 3rd, Mohler, J. L. & Whang, Y. E. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate 66, 1292–1301 (2006).

    Article  CAS  Google Scholar 

  75. Frietze, S., Lupien, M., Silver, P. A. & Brown, M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res. 68, 301–306 (2008).

    Article  CAS  Google Scholar 

  76. Zhao, Q. et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nature Struct. Mol. Biol. 16, 304–311 (2009).

    Article  CAS  Google Scholar 

  77. Patnaik, D. et al. Substrate specificity and kinetic mechanism of mammalian G9a histone H3 methyltransferase. J. Biol. Chem. 279, 53248–53258 (2004).

    Article  CAS  Google Scholar 

  78. Chin, H. G., Patnaik, D., Esteve, P.-O., Jacobsen, S. E. & Pradhan, S. Catalytic properties and kinetic mechanism of human recombinant lys-9 histone H3 methyltransferase SUV39H1: participation of the chromodomain in enzymatic catalysis. Biochemistry 45, 3272–3284 (2006).

    Article  CAS  Google Scholar 

  79. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3–9. Nature Chem. Biol. 1, 143–145 (2005).

    Article  CAS  Google Scholar 

  80. Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473–481 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to K. Shiosaki, C. T. Walsh, H. R. Horvitz, Y. Zhang, and R. Gould for their insights, constant support and encouragement. We also thank K. Boater, E. Olhava, L. Jin and T. Luly for expert help in preparation of this manuscript.

Author information

Authors and Affiliations

  1. Epizyme, Inc., 840 Memorial Drive, Cambridge, 02139, Massachussets, USA

    Robert A. Copeland, Michael E. Solomon & Victoria M. Richon

Authors
  1. Robert A. Copeland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Solomon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victoria M. Richon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Copeland.

Ethics declarations

Competing interests

R.A.C. and V.M.R. are employees of Epizyme. M.E.S. is a paid consultant of Epizyme.

Related links

Related links

FURTHER INFORMATION

Author's homepage

Glossary

Epigenetics

A stably heritable change in phenotype or gene expression in an organism or cell, resulting from changes in a chromosome that are not caused by a change in DNA sequence. The process of eukaryotic cell differentiation is one of the most well-known examples of epigenetic changes.

Target class

A group of proteins that are related by a common type of drug-binding pocket, but sufficiently diverse that selective inhibition of specific proteins can be achieved, using medicinal chemical elaboration of the basic chemotype structures.

SAM

S-adenosyl-L-methionine, the universal methyl group donor of all enzymatic methyltransferase reactions.

SAH

S-adenosyl-L-homocysteine, the universal product of all enzymatic methyltransferase reactions, formed by methyl group transfer from S-adenosyl-L-methionine.

General base catalysis

A mechanism that can occur in enzyme catalysis, in which a basic group accepts protons from a substrate molecule, usually to stabilize a charged transition-state species.

Structure–activity relationship

The relationship between the chemical structure of a compound and its pharmacological activity.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Copeland, R., Solomon, M. & Richon, V. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov 8, 724–732 (2009). https://doi.org/10.1038/nrd2974

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2974

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing