Conformational dynamics underlies different functions of human KDM7 histone demethylases
The human KDM7 subfamily histone H3 Nϵ‐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 fi...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2019
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| _version_ | 1797103307601215488 |
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| author | Chaturvedi, S Ramanan, R Waheed, S Ainsley, J Evison, M Ames, J Schofield, C Karabencheva-Christova, T Christov, C |
| author_facet | Chaturvedi, S Ramanan, R Waheed, S Ainsley, J Evison, M Ames, J Schofield, C Karabencheva-Christova, T Christov, C |
| author_sort | Chaturvedi, S |
| collection | OXFORD |
| description | The human KDM7 subfamily histone H3 Nϵ‐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. |
| first_indexed | 2024-03-07T06:18:15Z |
| format | Journal article |
| id | oxford-uuid:f1d384dc-5d8e-4844-8273-63e980cc524f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:18:15Z |
| publishDate | 2019 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:f1d384dc-5d8e-4844-8273-63e980cc524f2022-03-27T11:59:01ZConformational dynamics underlies different functions of human KDM7 histone demethylasesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f1d384dc-5d8e-4844-8273-63e980cc524fEnglishSymplectic Elements at OxfordWiley2019Chaturvedi, SRamanan, RWaheed, SAinsley, JEvison, MAmes, JSchofield, CKarabencheva-Christova, TChristov, CThe human KDM7 subfamily histone H3 Nϵ‐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. |
| spellingShingle | Chaturvedi, S Ramanan, R Waheed, S Ainsley, J Evison, M Ames, J Schofield, C Karabencheva-Christova, T Christov, C Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title | Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title_full | Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title_fullStr | Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title_full_unstemmed | Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title_short | Conformational dynamics underlies different functions of human KDM7 histone demethylases |
| title_sort | conformational dynamics underlies different functions of human kdm7 histone demethylases |
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