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首页> 美国卫生研究院文献>Nucleic Acids Research >NAR Breakthrough Article: Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation
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NAR Breakthrough Article: Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation

机译：NAR突破性文章：人类RNA N6-甲基腺嘌呤脱甲基酶ALKBH5的结构为其核酸识别和脱甲基化机理提供了见识

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摘要

ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N6-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66–292) to 2.0 Å resolution. ALKBH566–292 has a double-stranded β-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD…H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (βIV–V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX–nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.
机译：ALKBH5是一种2-氧戊二酸酯（2OG）和铁依赖铁的核酸氧化酶（NAOX），可催化RNA中N 6 -甲基腺嘌呤的去甲基化。 ALKBH5在缺氧条件下上调，在精子发生中起作用。我们描述了人类ALKBH5（残基66-292）至2.0分辨率的晶体结构。在其他2OG和铁依赖性加氧酶家族成员中观察到，ALKBH566–292具有双链β-螺旋核心折叠。活性位点金属由HXD…H基序（包含残基His204，Asp206和His266）和三个水分子八面体配位。 ALKBH5与其他NAOX共享一个核苷酸识别盖并保留了活性位点残基。 ALKBH5中的一个大环（βIV–V）占据与脂肪团和肥胖相关蛋白的L1环类似的区域，该区域被提议赋予单链RNA选择性。出乎意料的是，观察到小分子抑制剂IOX3共价连接到位于活性位点外部的Cys200侧链。根据其他NAOX核酸复合物将底物建模到活性位点中，发现保守的残基对于识别和去甲基化机制很重要。结构上的见解将有助于开发对NAOX有选择性的抑制剂，用作功能探针和治疗益处。

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