5LV3

Crystal structure of mouse CARM1 in complex with ligand LH1561Br

Summary for 5LV3

• Entry DOI: 10.2210/pdb5lv3/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, S-ADENOSYL-L-HOMOCYSTEINE, 5-[[2-[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]ethylamino]methyl]-4-azanyl-1-[2-(4-bromanylphenoxy)ethyl]pyrimidin-2-one, ... (4 entities in total)
• Functional Keywords: protein arginine methyltransferase, catalytic domain, chromatin regulator, mrna processing, mrna splicing, nucleus, s-adenosyl-l-methionine, transcription, transcription regulation, transferase
• Biological source: Mus musculus (House Mouse)
• Cellular location: Nucleus: Q9WVG6
• Total number of polymer chains: 4
• Total formula weight: 165375.53

Authors

Cura, V.,Marechal, N.,Troffer-Charlier, N.,Halby, L.,Arimondo, P.,Bonnefond, L.,Cavarelli, J. (deposition date: 2016-09-12, release date: 2017-09-20, Last modification date: 2024-01-17)

Primary citation

Halby, L.,Marechal, N.,Pechalrieu, D.,Cura, V.,Franchini, D.M.,Faux, C.,Alby, F.,Troffer-Charlier, N.,Kudithipudi, S.,Jeltsch, A.,Aouadi, W.,Decroly, E.,Guillemot, J.C.,Page, P.,Ferroud, C.,Bonnefond, L.,Guianvarc'h, D.,Cavarelli, J.,Arimondo, P.B.
Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.
Philos. Trans. R. Soc. Lond., B, Biol. Sci., 373:-, 2018

PubMed Abstract: DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound and its derivative showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound binds to the PRMT4 active site, displacing strongly the -adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

PubMed: 29685976
DOI: 10.1098/rstb.2017.0072

Experimental method

X-RAY DIFFRACTION (1.8 Å)