Structure-Based Design of Inhibitors of the m6A-RNA Writer Enzyme METTL3

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-06-14 DOI:10.1021/acsbiomedchemau.3c00023
Rajiv Kumar Bedi, Danzhi Huang, Yaozong Li and Amedeo Caflisch*, 
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引用次数: 1

Abstract

Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N6-methyladenosine (m6A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m6A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay. There is increasing evidence for an oncogenic role of METTL3 in acute myeloid leukemia. Here, we use structural and dynamic details of the catalytic subunit METTL3 for developing small-molecule inhibitors that compete with SAM. Starting from a hit identified by high-throughput docking, protein crystallography and molecular dynamics simulations were employed to guide the optimization of inhibitory activity. The potency was successfully improved by 8000-fold as measured by a homogeneous time-resolved fluorescence assay. The optimized compound is selective against the off-targets RNA methyltransferases METTL1 and METTL16.

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m6A-RNA写入酶METTL3抑制剂的结构设计
甲基转移酶样3(METTL3)和METTL14形成异二聚体复合物,催化最丰富的内部信使核糖核酸修饰N6-甲基腺苷(m6A)。METTL3是结合共底物S-腺苷甲硫氨酸(SAM)的催化亚基,而METTL14参与mRNA结合。m6A修饰提供了对基因表达的转录后水平控制,因为它几乎影响mRNA生命周期的所有阶段,包括剪接、核输出、翻译和衰变。越来越多的证据表明METTL3在急性髓系白血病中具有致癌作用。在这里,我们使用催化亚基METTL3的结构和动力学细节来开发与SAM竞争的小分子抑制剂。从高通量对接确定的命中开始,蛋白质晶体学和分子动力学模拟被用于指导抑制活性的优化。通过均匀时间分辨荧光测定法测量,效价成功地提高了8000倍。优化的化合物对脱靶RNA甲基转移酶METTL1和METTL16具有选择性。
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ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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