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Selectively Disrupting m6A-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 15 618-625 (2020)

Cited: 8 times
EuropePMC logo PMID: 32101404

Abstract

We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (m6A) 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 m6A. 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 m6A reader domains. The structural information is useful for the design of modulators of m6A recognition by YTHDC1.

Reviews citing this publication (2)

  1. Targeting the RNA demethylase FTO for cancer therapy. Zhou LL, Xu H, Huang Y, Yang CG. RSC Chem Biol 2 1352-1369 (2021)
  2. Characterization of epitranscriptome reader proteins experimentally and in silico: Current knowledge and future perspectives beyond the YTH domain. Miller LG, Demny M, Tamamis P, Contreras LM. Comput Struct Biotechnol J 21 3541-3556 (2023)

Articles citing this publication (6)

  1. Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation. Lee JH, Wang R, Xiong F, Krakowiak J, Liao Z, Nguyen PT, Moroz-Omori EV, Shao J, Zhu X, Bolt MJ, Wu H, Singh PK, Bi M, Shi CJ, Jamal N, Li G, Mistry R, Jung SY, Tsai KL, Ferreon JC, Stossi F, Caflisch A, Liu Z, Mancini MA, Li W. Mol Cell 81 3368-3385.e9 (2021)
  2. Probing ligand binding of endothiapepsin by `temperature-resolved' macromolecular crystallography. Huang CY, Aumonier S, Engilberge S, Eris D, Smith KML, Leonarski F, Wojdyla JA, Beale JH, Buntschu D, Pauluhn A, Sharpe ME, Metz A, Olieric V, Wang M. Acta Crystallogr D Struct Biol 78 964-974 (2022)
  3. Fast fragment- and compound-screening pipeline at the Swiss Light Source. Kaminski JW, Vera L, Stegmann DP, Vering J, Eris D, Smith KML, Huang CY, Meier N, Steuber J, Wang M, Fritz G, Wojdyla JA, Sharpe ME. Acta Crystallogr D Struct Biol 78 328-336 (2022)
  4. Fragment Ligands of the m6A-RNA Reader YTHDF2. Nai F, Nachawati R, Zálešák F, Wang X, Li Y, Caflisch A. ACS Med Chem Lett 13 1500-1509 (2022)
  5. Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis. Wang X, Chen Q, Bing Z, Zhou S, Xu Z, Hou Y, Zhao Y, Zhao S, Wang T. Int J Biol Sci 19 4672-4688 (2023)
  6. Recent Advances of RNA m6A Modifications in Cancer Immunoediting and Immunotherapy. Ma S, Barr T, Yu J. Cancer Treat Res 190 49-94 (2023)


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