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Protein methyltransferases as a target class for drug discovery

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.


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.

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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.


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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.

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Correspondence to Robert A. Copeland.

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

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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.


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


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.

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

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