Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase

Wyatt W. Yue; Viktorija Hozjan; Wei Ge; Christoph Loenarz; Christopher D O Cooper; Christopher J. Schofield; Kathryn L. Kavanagh; Udo Oppermann; Michael A. McDonough

doi:10.1016/j.febslet.2009.12.055

Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase

Wyatt W. Yue, Viktorija Hozjan, Wei Ge, Christoph Loenarz, Christopher D O Cooper, Christopher J. Schofield, Kathryn L. Kavanagh, Udo Oppermann, Michael A. McDonough

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

37 Citations (Scopus)

Abstract

Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an N^ε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific N^ε-methyl lysine demethylase subfamilies.

Original language	English
Pages (from-to)	825-830
Number of pages	6
Journal	FEBS Letters
Volume	584
Issue number	4
DOIs	https://doi.org/10.1016/j.febslet.2009.12.055
Publication status	Published - Feb 2010
Externally published	Yes

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@article{7cbfd170b5f446d2a9f57fd215e15d07,

title = "Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase",

abstract = "Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an Nε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific Nε-methyl lysine demethylase subfamilies.",

keywords = "2-Oxoglutarate oxygenase, Epigenetic modification, Histone lysine demethylase, JmjC, Transcriptional regulation",

author = "Yue, \{Wyatt W.\} and Viktorija Hozjan and Wei Ge and Christoph Loenarz and Cooper, \{Christopher D O\} and Schofield, \{Christopher J.\} and Kavanagh, \{Kathryn L.\} and Udo Oppermann and McDonough, \{Michael A.\}",

year = "2010",

month = feb,

doi = "10.1016/j.febslet.2009.12.055",

language = "English",

volume = "584",

pages = "825--830",

journal = "FEBS Letters",

issn = "0014-5793",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

TY - JOUR

T1 - Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase

AU - Yue, Wyatt W.

AU - Hozjan, Viktorija

AU - Ge, Wei

AU - Loenarz, Christoph

AU - Cooper, Christopher D O

AU - Schofield, Christopher J.

AU - Kavanagh, Kathryn L.

AU - Oppermann, Udo

AU - McDonough, Michael A.

PY - 2010/2

Y1 - 2010/2

N2 - Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an Nε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific Nε-methyl lysine demethylase subfamilies.

AB - Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an Nε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific Nε-methyl lysine demethylase subfamilies.

KW - 2-Oxoglutarate oxygenase

KW - Epigenetic modification

KW - Histone lysine demethylase

KW - JmjC

KW - Transcriptional regulation

UR - https://www.scopus.com/pages/publications/77649270417

UR - http://febs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)1873-3468/

U2 - 10.1016/j.febslet.2009.12.055

DO - 10.1016/j.febslet.2009.12.055

M3 - Article

C2 - 20067792

AN - SCOPUS:77649270417

SN - 0014-5793

VL - 584

SP - 825

EP - 830

JO - FEBS Letters

JF - FEBS Letters

IS - 4

ER -

Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase

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