Structural highlights
Function
[YTDC1_HUMAN] RNA-binding protein that regulates alternative splice site selection.[1]
Publication Abstract from PubMed
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.
Selectively Disrupting m(6)A-Dependent Protein-RNA Interactions with Fragments.,Bedi RK, Huang D, Wiedmer L, Li Y, Dolbois A, Wojdyla JA, Sharpe ME, Caflisch A, Sledz P ACS Chem Biol. 2020 Mar 2. doi: 10.1021/acschembio.9b00894. PMID:32101404[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, Rafalska I, Heinrich B, Bujnicki JM, Allain FH, Stamm S. The YTH domain is a novel RNA binding domain. J Biol Chem. 2010 May 7;285(19):14701-10. doi: 10.1074/jbc.M110.104711. Epub 2010, Feb 18. PMID:20167602 doi:http://dx.doi.org/10.1074/jbc.M110.104711
- ↑ Bedi RK, Huang D, Wiedmer L, Li Y, Dolbois A, Wojdyla JA, Sharpe ME, Caflisch A, Sledz P. Selectively Disrupting m(6)A-Dependent Protein-RNA Interactions with Fragments. ACS Chem Biol. 2020 Mar 2. doi: 10.1021/acschembio.9b00894. PMID:32101404 doi:http://dx.doi.org/10.1021/acschembio.9b00894
