@article{bibcite_684,
  author = {I. Corbeski and R. K. Bedi and C. M. Matter and F. Stamm and E. Bochenkova and M. Herok and M. J. Hartshorn and A. Caflisch},
  title = {Ligand-Induced Opening of a Cryptic Pocket in METTL14},
  abstract = {<p>The complex of methyltransferase-like proteins 3 and 14 (METTL3{\textendash}14) is the main human enzyme that deposits the most abundant internal mRNA modification, N6-methyladenosine (m6A). In the heterodimeric complex, METTL3 acts as a catalytic subunit while METTL14 is involved in mRNA binding and complex stabilization. Here, we present the discovery of small-molecule ligands that bind to a cryptic pocket in METTL14 by protein crystallography. A comparative analysis of crystal structures revealed that the METTL14 cryptic pocket is closed in the apo structure of METTL3{\textendash}14, and in the structures of METTL3{\textendash}14 in the complex with the cosubstrate S-adenosyl-methionine (SAM) and a large number of SAM-competitive inhibitors. We first discovered compounds 1 and 2 that bind to both the SAM pocket in METTL3 and the cryptic pocket in METTL14. With this structural information, we designed compound 3 that binds only to the METTL14 cryptic pocket. Compound 3 does not inhibit the catalytic activity of METTL3{\textendash}14 but can be used as an anchor for heterobifunctional molecules. We propose a route for its further development into heterobifunctional ligands, e.g., proteolysis targeting chimeras (PROTACs).</p>},
  year = {2026},
  journal = {ACS Bio \& Med Chem Au},
  volume = {6},
  pages = {130-144},
  month = {2026 Mar 10},
  url = {https://pubs.acs.org/doi/10.1021/acsbiomedchemau.5c00184},
  doi = {10.1021/acsbiomedchemau.5c00184},
  language = {eng},
}