Selectively Disrupting m6A-Dependent Protein-RNA Interactions with Fragments
Selectively Disrupting m6A-Dependent Protein-RNA Interactions with Fragments
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DOI：
10.1021/acschembio.9b00894
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发表时间：
2020-03-20
影响因子：
4
通讯作者：
Sledz, Pawel
中科院分区：
文献类型：
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作者：
Bedi, Rajiv Kumar;Huang, Danzhi;Sledz, Pawel
我们报道了人类YTHDC1结构域的小分子配体的晶体学分析，该结构域识别RNA中的n6甲基化腺嘌呤（m(6) a）。这30种结合剂是片段（分子量< 300 g mol(-1)），代表了通过虚拟筛选鉴定的10种不同的化学型。尽管结合位点环（429-439残基）结构紊乱，但30个片段中的大多数都模拟了m(6)A的-NHCH3基团的两个主要相互作用。这些相互作用是与Ser378主链羰基的氢键和与色氨酸笼的范德华接触。不同的化学基团参与了保守的结合基序。一些片段对YTHDC1表现出良好的配体效率和对其他m(6)A阅读器结构域的选择性。该结构信息可用于YTHDC1识别m(6)A调制器的设计。
We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (m(6)A) in RNA. The 30 binders are fragments (molecular weight < 300 g mol(-1)) that represent 10 different chemotypes identified by virtual screening. Despite the structural disorder of the binding site loop (residues 429-439), most of the 30 fragments emulate the two main interactions of the -NHCH3 group of m(6)A. These interactions are the hydrogen bond to the backbone carbonyl of Ser378 and the van der Waals contacts with the tryptophan cage. Different chemical groups are involved in the conserved binding motifs. Some of the fragments show favorable ligand efficiency for YTHDC1 and selectivity against other m(6)A reader domains. The structural information is useful for the design of modulators of m(6)A recognition by YTHDC1.