Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

Shobhit Chaturvedi; Rajeev Ramanan; Sodiq O. Waheed; Jon Ainsley; Martin Evison; Jenny Ames; Christopher J. Schofield; Tatyana Karabencheva-Christova; Christo Christov

doi:10.1002/chem.201900492

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

Shobhit Chaturvedi, Rajeev Ramanan, Sodiq O. Waheed, Jon Ainsley, Martin Evison, Jenny Ames, Christopher J. Schofield, Tatyana Karabencheva-Christova, Christo Christov

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	5422-5426
Number of pages	5
Journal	Chemistry - A European Journal
Volume	25
Issue number	21
Early online date	26 Mar 2019
DOIs	https://doi.org/10.1002/chem.201900492
Publication status	Published - 11 Apr 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Histone Demethylases
Conformational Dynamics
KDM7
Molecular Dynamics
non-heme iron and 2-oxoglutarate oxygenases
QM/MM molecular modeling

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title = "Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases",

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.",

keywords = "Histone Demethylases, Conformational Dynamics, KDM7, Molecular Dynamics, non-heme iron and 2-oxoglutarate oxygenases, QM/MM molecular modeling",

author = "Shobhit Chaturvedi and Rajeev Ramanan and Waheed, \{Sodiq O.\} and Jon Ainsley and Martin Evison and Jenny Ames and Schofield, \{Christopher J.\} and Tatyana Karabencheva-Christova and Christo Christov",

year = "2019",

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doi = "10.1002/chem.201900492",

language = "English",

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AU - Chaturvedi, Shobhit

AU - Ramanan, Rajeev

AU - Waheed, Sodiq O.

AU - Ainsley, Jon

AU - Evison, Martin

AU - Ames, Jenny

AU - Schofield, Christopher J.

AU - Karabencheva-Christova, Tatyana

AU - Christov, Christo

PY - 2019/4/11

Y1 - 2019/4/11

N2 - 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.

AB - 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.

KW - Histone Demethylases

KW - Conformational Dynamics

KW - KDM7

KW - Molecular Dynamics

KW - non-heme iron and 2-oxoglutarate oxygenases

KW - QM/MM molecular modeling

UR - https://www.scopus.com/pages/publications/85063441505

U2 - 10.1002/chem.201900492

DO - 10.1002/chem.201900492

M3 - Article

SN - 0947-6539

VL - 25

SP - 5422

EP - 5426

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 21

ER -

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

Abstract

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Keywords

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