Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Swiss Light Source, Paul Scherrer Institute, 5232 Villigen, Switzerland.
ACS Chem Biol. 2020 Mar 20;15(3):618-625. doi: 10.1021/acschembio.9b00894. Epub 2020 Mar 2.
We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (mA) in RNA. The 30 binders are fragments (molecular weight < 300 g mol) 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 -NHCH group of mA. 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 mA reader domains. The structural information is useful for the design of modulators of mA recognition by YTHDC1.
我们报告了人类 YTHDC1 结构域识别 RNA 中 N6-甲基腺嘌呤（mA）的小分子配体的晶体学分析。这 30 个结合物是通过虚拟筛选鉴定的 10 种不同化学型的片段（分子量<300 克摩尔）。尽管结合位点环（残基 429-439）的结构无序，但大多数 30 个片段模拟了 mA 的-NHCH 基团的两个主要相互作用。这些相互作用是氢键与 Ser378 的骨架羰基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。一些片段显示出对 YTHDC1 的有利配体效率和对其他 mA 读取器结构域的选择性。这些结构信息有助于设计 YTHDC1 识别 mA 的调节剂。
