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Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.

Publication ,  Journal Article
Yu, W; Chory, EJ; Wernimont, AK; Tempel, W; Scopton, A; Federation, A; Marineau, JJ; Qi, J; Barsyte-Lovejoy, D; Yi, J; Marcellus, R; Iacob, RE ...
Published in: Nature communications
January 2012

Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

January 2012

Volume

3

Start / End Page

1288

Related Subject Headings

  • Surface Plasmon Resonance
  • Substrate Specificity
  • Structure-Activity Relationship
  • Phenylurea Compounds
  • Methyltransferases
  • Kinetics
  • Humans
  • Histone-Lysine N-Methyltransferase
  • Catalytic Domain
  • Catalysis
 

Citation

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Yu, W., Chory, E. J., Wernimont, A. K., Tempel, W., Scopton, A., Federation, A., … Schapira, M. (2012). Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nature Communications, 3, 1288. https://doi.org/10.1038/ncomms2304
Yu, Wenyu, Emma J. Chory, Amy K. Wernimont, Wolfram Tempel, Alex Scopton, Alexander Federation, Jason J. Marineau, et al. “Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.Nature Communications 3 (January 2012): 1288. https://doi.org/10.1038/ncomms2304.
Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nature communications. 2012 Jan;3:1288.
Yu, Wenyu, et al. “Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.Nature Communications, vol. 3, Jan. 2012, p. 1288. Epmc, doi:10.1038/ncomms2304.
Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J, Marcellus R, Iacob RE, Engen JR, Griffin C, Aman A, Wienholds E, Li F, Pineda J, Estiu G, Shatseva T, Hajian T, Al-Awar R, Dick JE, Vedadi M, Brown PJ, Arrowsmith CH, Bradner JE, Schapira M. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nature communications. 2012 Jan;3:1288.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

January 2012

Volume

3

Start / End Page

1288

Related Subject Headings

  • Surface Plasmon Resonance
  • Substrate Specificity
  • Structure-Activity Relationship
  • Phenylurea Compounds
  • Methyltransferases
  • Kinetics
  • Humans
  • Histone-Lysine N-Methyltransferase
  • Catalytic Domain
  • Catalysis