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Selectively Disrupting m$^{6}$A-Dependent Protein-RNA Interactions with Fragments


Bedi, Rajiv Kumar; Huang, Danzhi; Wiedmer, Lars; Li, Yaozong; Dolbois, Aymeric; Wojdyla, Justyna Aleksandra; Sharpe, May Elizabeth; Caflisch, Amedeo; Sledz, Pawel (2020). Selectively Disrupting m$^{6}$A-Dependent Protein-RNA Interactions with Fragments. ACS Chemical Biology, 15(3):618-625.

Abstract

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 -NHCH$_{3}$ 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.

Abstract

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 -NHCH$_{3}$ 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Language:English
Date:20 March 2020
Deposited On:23 Jul 2020 10:23
Last Modified:29 Jul 2020 15:29
Publisher:American Chemical Society (ACS)
ISSN:1554-8929
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acschembio.9b00894
PubMed ID:32101404

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