6T12

Crystal structure of YTHDC1 with fragment 30 (DHU_DC1_220)

Summary for 6T12

• Entry DOI: 10.2210/pdb6t12/pdb
• Descriptor: YTHDC1, ~{N},2,3-trimethyl-1~{H}-indole-5-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: fragment, complex, ythdc1, epitranscriptomic, rna binding protein
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 42915.20

Authors

Bedi, R.K.,Huang, D.,Sledz, P.,Caflisch, A. (deposition date: 2019-10-03, release date: 2020-03-04, Last modification date: 2024-01-24)

Primary citation

Bedi, R.K.,Huang, D.,Wiedmer, L.,Li, Y.,Dolbois, A.,Wojdyla, J.A.,Sharpe, M.E.,Caflisch, A.,Sledz, P.
Selectively Disrupting m6A-Dependent Protein-RNA Interactions with Fragments.
Acs Chem.Biol., 15:618-625, 2020

PubMed Abstract: 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.

PubMed: 32101404
DOI: 10.1021/acschembio.9b00894

Experimental method

X-RAY DIFFRACTION (1.46 Å)