Chemical Biology of Protein N‐Terminal Methyltransferases

Huang, Rong

doi:10.1002/cbic.201800615

Cited by 21 publications

(40 citation statements)

References 60 publications

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“…8–10 Recently, regulator of chromatin condensation 1 (RCC1), the tumor suppressor retinoblastoma 1 (RB1), oncoprotein SET, centromere protein A/B (CENP-A/B), damaged DNA-binding protein 2 (DDB2), and poly(ADP-ribose) polymerase 3 (PARP3) have been reported to undergo N-terminal methylation. 4,11–17 The function of α -N-terminal methylation is traditionally inferred to regulate protein stability and protein–protein interaction. Recently, its role in protein–DNA interaction has been uncovered in chromosome segregation, mitosis, and DNA damage repair.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

et al. 2019

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Protein N-terminal methyltransferase 1 (NTMT1) plays an important role in regulating mitosis and DNA repair. Here, we describe the discovery of a potent NTMT1 bisubstrate inhibitor 4 (IC50 = 35 ± 2 nM) that exhibits greater than 100-fold selectivity against a panel of methyltransferases. We also report the first crystal structure of NTMT1 in complex with an inhibitor, which revealed that 4 occupies substrate and cofactor binding sites of NTMT1.

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Section: Introductionmentioning

confidence: 99%

Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

et al. 2019

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“…1 The Tae1/NTMT1/NTMT2 α-N-terminal methyltransferases are highly conserved between yeast and humans and the enzymes recognize substrates with similar N-terminal sequence motifs, X 1 -P 2 -[K/R] 3 (X position could be A, S, G or P), hereinafter referred to as the canonical N-terminal motif. 2,3 In the motif, the initiating methionine (iMet) is commonly removed during protein maturation hence leaving the α-amino group on the X amino acid exposed which is subsequently targeted for methylation.…”

Section: Introductionmentioning

confidence: 99%

Discovering the N-terminal Methylome by Repurposing of Proteomic Datasets

Chen

Sobreira²,

Hall

et al. 2021

Preprint

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Protein α-N-methylation is an underexplored post-translational modification involving the covalent addition of methyl groups to the free α-amino group at protein N-termini. To systematically explore the extent of α-N-terminal methylation in yeast and humans, we reanalyzed publicly accessible proteomic datasets to identify N-terminal peptides contributing to the α-N-terminome. This repurposing approach found evidence of α-N-methylation of established and novel protein substrates with canonical N-terminal motifs of established α-N-terminal methyltransferases, NTMT1/2 for humans, and Tae1 for yeast. NTMT1/2 has been implicated in cancer and aging processes. Moreover, α-N-methylation of non-canonical sequences was surprisingly prevalent, suggesting unappreciated and cryptic methylation events. Analysis of the amino acid frequencies of α-N-methylated peptides revealed a [S]1-[S/A/Q]2 pattern in yeast and [A/G/N]1-[A/S/V]2-[A]3 in humans, which differs from the canonical motif. We delineated the distribution of the two types of prevalent N-terminal modifications, acetylation and methylation, on amino acids at the 1st position. We tested three potentially methylated proteins and confirmed the α-N-terminal methylation of Hsp31. The other two proteins, Vma1 and Ssa3, were found to be predominantly acetylated indicating proteomic searching for α-N-terminal methylation can be difficult due to experimental approach or the methylated peptides are rare. This study demonstrates the feasibility of reprocessing proteomic data for global α-N-terminal methylome investigations. (Raw data deposited with PRIDE identifier: PXD022833)

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“…Protein α -N-terminal methylation has been known for nearly four decades since it was first uncovered on bacteria ribosomal proteins L33 4,5 . The identification of N-terminal methyltransferase 1 (NTMT1/NRMT1) unveiled the first methylation writer for human protein α…”

Section: Introductionmentioning

confidence: 99%

“…Protein α -N-terminal methylation was originally proposed to regulate protein-protein interactions since the methylated proteins initially identified were involved in large macromolecular complexes including histone proteins, cytochrome c-557, and myosin light chain proteins 4,14 . Recent discoveries have demonstrated its relevance in protein-DNA interactions, as shown in strengthening the interactions of chromatin with centromere protein A (CENPA) and regulator of chromosome condensation 1 (RCC1), as well as DNA damage-binding protein 2 (DDB2) to DNA damage foci [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies

et al. 2020

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Protein N-terminal methyltransferases (NTMTs) methylate the α-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitor for NTMT1/2. Biochemical and cocrystallization studies manifest that BM30 (with a half-maximal inhibitory concentration of 0.89 ± 0.10 μM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. BM30 exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 MTs, indicating its potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analogue DC432 (IC50 of 54 ± 4 nM) decreases the N-terminal methylation level of the regulator of chromosome condensation 1 and SET proteins in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in the future.

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Chemical Biology of Protein N‐Terminal Methyltransferases

Cited by 21 publications

References 60 publications

Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

Discovering the N-terminal Methylome by Repurposing of Proteomic Datasets

Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies

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