Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18450%2F15%3A50004384" target="_blank" >RIV/62690094:18450/15:50004384 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1002/chem.201502983" target="_blank" >http://dx.doi.org/10.1002/chem.201502983</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/chem.201502983" target="_blank" >10.1002/chem.201502983</a>

Result language

angličtina

Original language name

Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

Original language description

JMJD2A catalyses the demethylation of di- and trimethylated lysine residues in histone tails and is a target for the development of new anticancer medicines. Mechanistic details of demethylation are yet to be elucidated and are important for the understanding of epigenetic processes. We have evaluated the initial step of histone demethylation by JMJD2A and demonstrate the dramatic effect of the protein environment upon oxygen binding using quantum mechanics/molecular mechanics (QM/MM) calculations. The changes in electronic structure have been studied for possible spin states and different conformations of O2 , using a combination of quantum and classical simulations. O2 binding to this histone demethylase is computed to occur preferentially as an end-on superoxo radical bound to a high-spin ferric centre, yielding an overall quintet ground state. The favourability of binding is strongly influenced by the surrounding protein: we have quantified this effect using an energy decomposition scheme into electrostatic and dispersion contributions. His182 and the methylated lysine assist while Glu184 and the oxoglutarate cofactor are deleterious for O2 binding. Charge separation in the superoxo-intermediate benefits from the electrostatic stabilization provided by the surrounding residues, stabilizing the binding process significantly. This work demonstrates the importance of the extended protein environment in oxygen binding, and the role of energy decomposition in understanding the physical origin of binding/recognition.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30108 - Toxicology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2015

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Chemistry - a European Journal

ISSN

0947-6539

e-ISSN

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Volume of the periodical

21

Issue of the periodical within the volume

52

Country of publishing house

DE - GERMANY

Number of pages

10

Pages from-to

18983-18992

UT code for WoS article

000368282100019

EID of the result in the Scopus database

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