Download Dioxygen Binding in the Active Site of Histone Demethylase

DOI: 10.1002/chem.201504536
Cover Profile
Dioxygen Binding in the Active Site of Histone Demethylase
JMJD2A and the Role of the Protein Environment
Wilian A. Cortopassi
Robert Simion
Charles E. Honsby
Tanos C. C. FranÅa
Robert S. Paton
Invited for the cover of this issue is the group of Robert S. Paton at the University of Oxford and his collaborators from
Brazil and the Czech Republic. The image depicts histone–enzyme complexation and the chemical interactions inside the
active site that define the mode of action. Read the full text of the article at 10.1002/chem.201502983.
In one word, how would you describe your research?
Residues. Our work focuses on using state of the art computational
techniques to understand the role of the protein environment of
an epigenetic “eraser” process. The lysine demethylation is a multistep reaction starting with the O2 binding. Our calculations
showed that even residues not directly bound to the iron active
site play an important role for the exergonic character for this initial step. The understanding of the energetic contribution of these
amino acids supports future studies on mutations and drug design
of epigenetic proteins.
What was the inspiration of this cover design?
The cover image was illustrated by Dr. Karl Harrison and captures
both the biological context of histone–enzyme complexation and
the chemical interactions inside the active site that define the
mode of action. Our work illustrates and quantifies the interactions
involved during oxygen binding, which is shown attached to the
iron center (in gold).
What future opportunities do you see (in the light of the
results presented in this paper)?
Now we have studied the first step of demethylation by JmjC proteins, highlighting the importance of non-local energy contributions from residues and substrate. Our next steps will involve understanding the structural basis for substrate selectivity within the
active site, and the full reaction coordinate. We are optimistic that
these computational insights into the mode of action of demethylation will be useful tools to explore enzyme mutants and in the rational design of small-molecule inhibitors.
Chem. Eur. J. 2015, 21, 18869
18869
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim