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Structural basis for substrate recognition by the human N-terminal methyltransferase 1.

Dong C, Mao Y, Tempel W, Qin S, Li L, Loppnau P, Huang R, Min J
Genes Dev 29 2343-8 (2015)
Related entries: 5e1b, 5e1m, 5e1o, 5e2a, 5e2b

Cited: 29 times
EuropePMC logo PMID: 26543161

Abstract

α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides, respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.

Reviews - 5e1d mentioned but not cited (2)

  1. Chemical Biology of Protein N-Terminal Methyltransferases. Huang R. Chembiochem 20 976-984 (2019)
  2. Unlocking the mysteries of alpha-N-terminal methylation and its diverse regulatory functions. Chen P, Huang R, Hazbun TR. J Biol Chem 299 104843 (2023)

Articles - 5e1d mentioned but not cited (4)

  1. Structural basis for substrate recognition by the human N-terminal methyltransferase 1. Dong C, Mao Y, Tempel W, Qin S, Li L, Loppnau P, Huang R, Min J. Genes Dev 29 2343-2348 (2015)
  2. An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2. Dong C, Dong G, Li L, Zhu L, Tempel W, Liu Y, Huang R, Min J. Commun Biol 1 183 (2018)
  3. Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies. Mackie BD, Chen D, Dong G, Dong C, Parker H, Schaner Tooley CE, Noinaj N, Min J, Huang R. J Med Chem 63 9512-9522 (2020)
  4. Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner. Dong G, Deng Y, Yasgar A, Yadav R, Talley D, Zakharov AV, Jain S, Rai G, Noinaj N, Simeonov A, Huang R. J Med Chem 65 12334-12345 (2022)


Reviews citing this publication (5)

  1. Post-translational Modifications of the Protein Termini. Chen L, Kashina A. Front Cell Dev Biol 9 719590 (2021)
  2. Methyltransferases: Functions and Applications. Abdelraheem E, Thair B, Varela RF, Jockmann E, Popadić D, Hailes HC, Ward JM, Iribarren AM, Lewkowicz ES, Andexer JN, Hagedoorn PL, Hanefeld U. Chembiochem 23 e202200212 (2022)
  3. Past, present, and perspectives of protein N-terminal methylation. Diaz K, Meng Y, Huang R. Curr Opin Chem Biol 63 115-122 (2021)
  4. Structure, Activity and Function of the Dual Protein Lysine and Protein N-Terminal Methyltransferase METTL13. Jakobsson ME. Life (Basel) 11 1121 (2021)
  5. Impact of Protein Nα-Modifications on Cellular Functions and Human Health. Chang YH. Life (Basel) 13 1613 (2023)

Articles citing this publication (18)

  1. α-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere. Sathyan KM, Fachinetti D, Foltz DR. Nat Commun 8 14678 (2017)
  2. Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase. Chen D, Li L, Diaz K, Iyamu ID, Yadav R, Noinaj N, Huang R. J Med Chem 62 10783-10797 (2019)
  3. Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1. Chen D, Dong G, Noinaj N, Huang R. J Med Chem 62 3773-3779 (2019)
  4. Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N-terminal trimethylation. Shields KM, Tooley JG, Petkowski JJ, Wilkey DW, Garbett NC, Merchant ML, Cheng A, Schaner Tooley CE. Protein Sci 26 1639-1652 (2017)
  5. 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)
  6. Facile synthesis of SAM-peptide conjugates through alkyl linkers targeting protein N-terminal methyltransferase 1. Zhang G, Huang R. RSC Adv 6 6768-6771 (2016)
  7. The ribosome: A hot spot for the identification of new types of protein methyltransferases. Clarke SG. J Biol Chem 293 10438-10446 (2018)
  8. Optimization of High-Throughput Methyltransferase Assays for the Discovery of Small Molecule Inhibitors. Dong G, Yasgar A, Peterson DL, Zakharov A, Talley D, Cheng KC, Jadhav A, Simeonov A, Huang R. ACS Comb Sci 22 422-432 (2020)
  9. Structure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1. Chen D, Dong G, Deng Y, Noinaj N, Huang R. ACS Med Chem Lett 12 485-493 (2021)
  10. In vivo methylation of OLA1 revealed by activity-based target profiling of NTMT1. Jia K, Huang G, Wu W, Shrestha R, Wu B, Xiong Y, Li P. Chem Sci 10 8094-8099 (2019)
  11. Design and characterization of PROTAC degraders specific to protein N-terminal methyltransferase 1. Zhou Q, Wu W, Jia K, Qi G, Sun XS, Li P. Eur J Med Chem 244 114830 (2022)
  12. Single-cell architecture and functional requirement of alternative splicing during hematopoietic stem cell formation. Wang F, Tan P, Zhang P, Ren Y, Zhou J, Li Y, Hou S, Li S, Zhang L, Ma Y, Wang C, Tang W, Wang X, Huo Y, Hu Y, Cui T, Niu C, Wang D, Liu B, Lan Y, Yu J. Sci Adv 8 eabg5369 (2022)
  13. Chemoproteomic Study Uncovers HemK2/KMT9 As a New Target for NTMT1 Bisubstrate Inhibitors. Chen D, Meng Y, Yu D, Noinaj N, Cheng X, Huang R. ACS Chem Biol 16 1234-1242 (2021)
  14. Biochemical Characterization and Structural Basis of Reactivity and Regioselectivity Differences between Burkholderia thailandensis and Burkholderia glumae 1,6-Didesmethyltoxoflavin N-Methyltransferase. Fenwick MK, Almabruk KH, Ealick SE, Begley TP, Philmus B. Biochemistry 56 3934-3944 (2017)
  15. Structure-Activity Relationship Studies of Venglustat on NTMT1 Inhibition. Deng Y, Dong G, Meng Y, Noinaj N, Huang R. J Med Chem 66 1601-1615 (2023)
  16. Multicomponent Oxidative Nitrile Thiazolidination Reaction for Selective Modification of N-terminal Dimethylation Posttranslational Modification. Emenike B, Donovan J, Raj M. J Am Chem Soc 145 16417-16428 (2023)
  17. Optimizing purification and activity assays of N-terminal methyltransferase complexes. Parker HV, Tooley JG, Schaner Tooley CE. Methods Enzymol 684 71-111 (2023)
  18. The comprehensive analysis of the prognostic and functional role of N-terminal methyltransferases 1 in pan-cancer. Tan L, Li W, Su Q. PeerJ 11 e16263 (2023)


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