Structure of Naegleria Tet-like dioxygenase (NgTet1) in complexes with a reaction intermediate 5-hydroxymethylcytosine DNA

Nucleic Acids Research
Hideharu HashimotoXiaodong Cheng

Abstract

The family of ten-eleven translocation (Tet) dioxygenases is widely distributed across the eukaryotic tree of life, from mammals to the amoeboflagellate Naegleria gruberi. Like mammalian Tet proteins, the Naegleria Tet-like protein, NgTet1, acts on 5-methylcytosine (5mC) and generates 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in three consecutive, Fe(II)- and α-ketoglutarate-dependent oxidation reactions. The two intermediates, 5hmC and 5fC, could be considered either as the reaction product of the previous enzymatic cycle or the substrate for the next cycle. Here we present a new crystal structure of NgTet1 in complex with DNA containing a 5hmC. Along with the previously solved NgTet1-5mC structure, the two complexes offer a detailed picture of the active site at individual stages of the reaction cycle. In the crystal, the hydroxymethyl (OH-CH2-) moiety of 5hmC points to the metal center, representing the reaction product of 5mC hydroxylation. The hydroxyl oxygen atom could be rotated away from the metal center, to a hydrophobic pocket formed by Ala212, Val293 and Phe295. Such rotation turns the hydroxyl oxygen atom away from the product conformation, and exposes the target CH2 toward...Continue Reading

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Citations

Aug 9, 2016·Chemical Reviews·Alexander C Drohat, Christopher T Coey
Dec 6, 2016·Nature Chemical Biology·Monica Yun LiuRahul M Kohli
Mar 30, 2017·Chemical Society Reviews·Yuqi ChenXiang Zhou
Oct 14, 2017·Bioinformatics·Konrad KrawczykPeter Minary
Jun 28, 2018·Briefings in Bioinformatics·Dongyang LiuYongchun Zuo
Apr 3, 2016·Genes & Development·Kasper Dindler Rasmussen, Kristian Helin
Apr 30, 2017·Experimental & Molecular Medicine·Jungeun AnMyunggon Ko
Aug 11, 2017·Biology Methods and Protocols·Peng ZhangM Cristina Cardoso
Jun 18, 2016·Current Opinion in Chemical Biology·Monica Yun LiuRahul M Kohli
Feb 18, 2018·Current Opinion in Chemical Biology·Jamie E DeNizioRahul M Kohli
Jun 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Evan J BurkeLana Saleh

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Methods Mentioned

BETA
X-ray

Software Mentioned

PyMol
PHENIX
HKL2000

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