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Modeling a New Water Channel That Allows SET9 to Dimethylate p53

Author

Listed:
  • Qifeng Bai
  • Yulin Shen
  • Xiaojun Yao
  • Fang Wang
  • Yuping Du
  • Qin Wang
  • Nengzhi Jin
  • Jun Hai
  • Tiejun Hu
  • Jinbo Yang

Abstract

SET9, a protein lysine methyltransferase, has been thought to be capable of transferring only one methyl group to target lysine residues. However, some reports have pointed out that SET9 can dimethylate Lys372 of p53 (p53-K372) and Lys4 of histone H3 (H3-K4). In order to understand how p53 can be dimethylated by SET9, we measured the radius of the channel that surrounds p53-K372, first on the basis of the crystal structure of SET9, and we show that the channel is not suitable for water movement. Second, molecular dynamic (MD) simulations were carried out for 204 ns on the crystal structure of SET9. The results show that water leaves the active site of SET9 through a new channel, which is made of G292, A295, Y305 and Y335. In addition, the results of molecular docking and MD simulations indicate that the new water channel continues to remain open when S-adenosyl-L-methionine (AdoMet) or S-adenosyl-L-homocysteine (AdoHcy) is bound to SET9. The changes in the radii of these two channels were measured in the equilibrium phase at the constant temperature of 300 K. The results indicate that the first channel still does not allow water to get into or out of the active site, but the new channel is large enough to allow this water to circulate. Our results indicate that water can be removed from the active site, an essential process for allowing the dimethylation reaction to occur.

Suggested Citation

  • Qifeng Bai & Yulin Shen & Xiaojun Yao & Fang Wang & Yuping Du & Qin Wang & Nengzhi Jin & Jun Hai & Tiejun Hu & Jinbo Yang, 2011. "Modeling a New Water Channel That Allows SET9 to Dimethylate p53," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-9, May.
  • Handle: RePEc:plo:pone00:0019856
    DOI: 10.1371/journal.pone.0019856
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    References listed on IDEAS

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    2. Brian D. Strahl & C. David Allis, 2000. "The language of covalent histone modifications," Nature, Nature, vol. 403(6765), pages 41-45, January.
    3. Jing Huang & Laura Perez-Burgos & Brandon J. Placek & Roopsha Sengupta & Mario Richter & Jean A. Dorsey & Stefan Kubicek & Susanne Opravil & Thomas Jenuwein & Shelley L. Berger, 2006. "Repression of p53 activity by Smyd2-mediated methylation," Nature, Nature, vol. 444(7119), pages 629-632, November.
    4. Bing Xiao & Chun Jing & Jonathan R. Wilson & Philip A. Walker & Nishi Vasisht & Geoff Kelly & Steven Howell & Ian A. Taylor & G. Michael Blackburn & Steven J. Gamblin, 2003. "Structure and catalytic mechanism of the human histone methyltransferase SET7/9," Nature, Nature, vol. 421(6923), pages 652-656, February.
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