ArticleProceedings of the National Academy of Sciences of the United States of America2016
A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- PRMT7 at the crossroads of cancer progression and therapeutic targeting (Review).Oncology reports · 2026Review
- Comparative genomics of nicotinic acetylcholine receptors reveals early divergence of the α6 subunit in cryptic Anopheles species.BMC genomics · 2026Article
- Structural determinants at KCNE4 position 145 govern Kv1.3 channel function.The Journal of general physiology · 2026Article
- Protein arginine methyltransferase 7 regulates the cell cycle and promotes the progression of prostate cancer.Oncology letters · 2025Article
- Review
- Regulation of protein arginine methyltransferase in osteoporosis: a narrative review.Frontiers in cell and developmental biology · 2025Review
- Advances in Protozoan Epigenetic Targets and Their Inhibitors for the Development of New Potential Drugs.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Structure-Activity Relationship Studies of Venglustat on NTMT1 Inhibition.Journal of medicinal chemistry · 2023Article
- Protein arginine methylation in viral infection and antiviral immunity.International journal of biological sciences · 2023Review
- The exquisite specificity of human protein arginine methyltransferase 7 (PRMT7) toward Arg-X-Arg sites.PloS one · 2023Article
- Protein arginine methyltransferases in protozoan parasites.Parasitology · 2022Review
- Structure and Function of Protein Arginine Methyltransferase PRMT7.Life (Basel, Switzerland) · 2021Review
- Chemoproteomic Study Uncovers HemK2/KMT9 As a New Target for NTMT1 Bisubstrate Inhibitors.ACS chemical biology · 2021Article
- Phosphoserine inhibits neighboring arginine methylation in the RKS motif of histone H3.Archives of biochemistry and biophysics · 2021Article
- Arginine Methyltransferases as Regulators of RNA-Binding Protein Activities in Pathogenic Kinetoplastids.Frontiers in molecular biosciences · 2021Review
- Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues.Journal of medicinal chemistry · 2020Article
- PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites.Nucleic acids research · 2020Article
- Structural Basis of Protein Arginine Methyltransferase Activation by a Catalytically Dead Homolog (Prozyme).Journal of molecular biology · 2020Article
- Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for NicotinamideJournal of medicinal chemistry · 2019Article
- Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level.Cellular and molecular life sciences : CMLS · 2019Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Trypanosoma brucei PRMT7 (TbPRMT7) is a protein arginine methyltransferase (PRMT) that strictly monomethylates various substrates, thus classifying it as a type III PRMT. However, the molecular basis of its unique product specificity has remained elusive. Here, we present the structure of TbPRMT7 in complex with its cofactor product S-adenosyl-l-homocysteine (AdoHcy) at 2.8 Å resolution and identify a glutamate residue critical for its monomethylation behavior. TbPRMT7 comprises the conserved methyltransferase and β-barrel domains, an N-terminal extension, and a dimerization arm. The active site at the interface of the N-terminal extension, methyltransferase, and β-barrel domains is stabilized by the dimerization arm of the neighboring protomer, providing a structural basis for dimerization as a prerequisite for catalytic activity. Mutagenesis of active-site residues highlights the importance of Glu181, the second of the two invariant glutamate residues of the double E loop that coordinate the target arginine in substrate peptides/proteins and that increase its nucleophilicity. Strikingly, mutation of Glu181 to aspartate converts TbPRMT7 into a type I PRMT, producing asymmetric dimethylarginine (ADMA). Isothermal titration calorimetry (ITC) using a histone H4 peptide showed that the Glu181Asp mutant has markedly increased affinity for monomethylated peptide with respect to the WT, suggesting that the enlarged active site can favorably accommodate monomethylated peptide and provide sufficient space for ADMA formation. In conclusion, these findings yield valuable insights into the product specificity and the catalytic mechanism of protein arginine methyltransferases and have important implications for the rational (re)design of PRMTs.
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