Abstract
Histone demethylases (KDMs) catalyze histone lysine demethylation, an important epigenetic process that controls gene expression in eukaryotes, and represent important cancer drug targets for cancer treatment. Demethylation of histone is comprised of sequential reaction steps including oxygen activation, decarboxylation, and demethylation. The initial oxygen binding and activation steps have been studied. However, the information on the complete catalytic reaction cycle is limited, which has impeded the structure-based design of inhibitors targeting KDMs. Here we report the mechanism of the complete reaction steps catalyzed by a representative nonheme iron αKG-dependent KDM, PHF8 using QM/MM approaches. The atomic-level understanding on the complete reaction mechanism of PHF8 would shed light on the structure-based design of selective inhibitors targeting KDMs to intervene in cancer epigenetics.
| Original language | English |
|---|---|
| Pages (from-to) | 7801-7811 |
| Number of pages | 11 |
| Journal | The Journal of Physical Chemistry B |
| Volume | 123 |
| Issue number | 37 |
| Early online date | 30 Aug 2019 |
| DOIs | |
| Publication status | Published - 19 Sept 2019 |
Bibliographical note
This is a computational study funded by the Invest NI project, in collaboration with Almac.
Access to Document
- Reaction Mechanism of Histone Demethylation in αKG-Dependent Non-Heme Iron Enzymes
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