Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

Chaturvedi, Shobhit, Ramanan, Rajeev, Waheed, Sodiq, Ainsley, Jon, Evison, Martin, Ames, Jenny, Schofield, Christopher, Karabencheva-Christova, Tatyana and Christov, Christo (2019) Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases. Chemistry - A European Journal, 25 (21). pp. 5422-5426. ISSN 0947-6539

[img] Text (Full text)
Chaturvedi et al - Conformational Dynamics AAM.pdf - Accepted Version
Restricted to Repository staff only until 26 March 2020.

Download (1MB) | Request a copy
Official URL: https://doi.org/10.1002/chem.201900492

Abstract

The human KDM7 subfamily histone H3 Nɛ‐methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates inter‐domain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X‐linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues. The calculations reveal key roles of a flexible protein environment in productive formation of enzyme‐substrate complexes and suggest targeting the flexible KDM7 linker region is of interest from a medicinal chemistry perspective.

Item Type: Article
Uncontrolled Keywords: Histone Demethylases, Conformational Dynamics, KDM7, Molecular Dynamics, non-heme iron and 2-oxoglutarate oxygenases, QM/MM molecular modeling
Subjects: C400 Genetics
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Paul Burns
Date Deposited: 12 Mar 2019 09:49
Last Modified: 30 Apr 2019 09:45
URI: http://nrl.northumbria.ac.uk/id/eprint/38375

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year

View more statistics


Policies: NRL Policies | NRL University Deposit Policy | NRL Deposit Licence