Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-stranded N6-Methyladenosine RNA Demethylation

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成果类型：

期刊论文

作者：

Xu, Chao;Liu, Ke;Tempel, Wolfram;Demetriades, Marina;Aik, WeiShen;...

通讯作者：

Min, Jinrong

作者机构：

[Tempel, Wolfram; Xu, Chao; Liu, Ke; Min, Jinrong] Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China.

[Xu, Chao; Liu, Ke; Min, Jinrong] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.

[Liu, Ke; Min, Jinrong] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England.

[Demetriades, Marina; Schofield, Christopher J.; Aik, WeiShen] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada.

通讯机构：

[Min, Jinrong] C

Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China.

语种：

英文

关键词：

Crystal Structure;Dioxygenase;Isothermal Titration Calorimetry (ITC);RNA Catalysis;RNA Methylation;Tricarboxylic Acid Cycle (TCA Cycle) (Krebs Cycle)

期刊：

Journal of Biological Chemistry

ISSN：

0021-9258

年：

2014

卷：

289

期：

页码：

17299-17311

DOI：

10.1074/jbc.M114.550350

基金类别：

Biotechnological and Biological Research CouncilUK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC); AbbVie; Boehringer IngelheimBoehringer Ingelheim; Canada Foundation for InnovationCanada Foundation for InnovationCGIAR; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Genome Canada through Ontario Genomics InstituteGenome Canada [OGI-055]; GlaxoSmithKlineGlaxoSmithKline; JanssenJohnson & Johnson USAJanssen Biotech Inc; Lilly CanadaEli Lilly; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; PfizerPfizer; TakedaTakeda Pharmaceutical Company Ltd; Wellcome TrustWellcome TrustEuropean Commission [092809/Z/10/Z]; Biotechnology and Biological Sciences Research CouncilUK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC) [BB/L009846/1] Funding Source: researchfish

机构署名：

本校为第一且通讯机构

院系归属：

生命科学学院

摘要：

N6-Methyladenosine (m6A) is the most prevalent internal RNA modification in eukaryotes. ALKBH5 belongs to the AlkB family of dioxygenases and has been shown to specifically demethylate m6A in single-stranded RNA. Here we report crystal structures of ALKBH5 in the presence of either its cofactors or the ALKBH5 inhibitor citrate. Catalytic assays demonstrate that the ALKBH5 catalytic domain can demethylate both single-stranded RNA and single-stranded DNA. We identify the TCA cycle intermediate citrate as a modest inhibitor of ALKHB5 (IC50, ∼488 ...

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Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-stranded N6-Methyladenosine RNA Demethylation

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