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Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases
Author(s) -
Chaturvedi Shobhit S.,
Ramanan Rajeev,
Waheed Sodiq O.,
Ainsley Jon,
Evison Martin,
Ames Jennifer M.,
Schofield Christopher J.,
KarabenchevaChristova Tatyana G.,
Christov Christo Z.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201900492
Subject(s) - epigenetics , histone , subfamily , substrate (aquarium) , phd finger , chemistry , demethylation , molecular dynamics , mutation , biology , stereochemistry , computational biology , biochemistry , gene , dna methylation , computational chemistry , gene expression , zinc finger , ecology , transcription factor
The human KDM7 subfamily histone H3 N ϵ ‐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 interdomain 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.