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Reference: Chang Y, et al. (2010) Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism. Biochem J 433(2):295-302

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Abstract

Saccharomyces cerevesiae Rph1 is a histone demethylase orthologous to human JMJD2A (Jumonji-domain-containing protein 2A) that can specifically demethylate tri- and di-methylated Lys(3) of histone H3. c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes. In the present work, we report the crystal structures of c-Rph1 in apo form and in complex with Ni(2)(+) and alpha-KG [2-oxoglutarate (alpha-ketoglutarate)]. The structure of c-Rph1 is composed of a JmjN (Jumonji N) domain, a long beta-hairpin, a mixed structural motif and a JmjC domain. The alpha-KG cofactor forms hydrogen-bonding interactions with the side chains of conserved residues, and the Ni(2)(+) ion at the active site is chelated by conserved residues and the cofactor. Structural comparison of Rph1 with JMJD2A indicates that the substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long beta-hairpin and the mixed structural motif; and the methylated Lys(3) of H3 is recognized by several conserved residues of the JmjC domain. In vitro biochemical results show that mutations of the key residues at the catalytic centre and in the substrate-binding cleft abolish the demethylase activity. In vivo growth phenotype analyses also demonstrate that these residues are essential for its functional roles in transcription elongation. Taken together, our structural and biological data provide insights into the molecular basis of the histone demethylase activity and the substrate specificity of Rph1.

Reference Type
Journal Article | Research Support, Non-U.S. Gov't
Authors
Chang Y, Wu J, Tong XJ, Zhou JQ, Ding J
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