7PUC

CARM1 in complex with EML981

Summary for 7PUC

• Entry DOI: 10.2210/pdb7puc/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, methyl 6-[4-[[~{N}-[(~{E})-3-[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]prop-2-enyl]carbamimidoyl]amino]butylcarbamoylamino]-4-oxidanyl-naphthalene-2-carboxylate, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protein arginine n-methyltransferase, prmt4, carm1, inhibitor, transcription
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 4
• Total formula weight: 166058.58

Authors

Marechal, N.,Cura, V.,Bonnefond, L.,Troffer-Charlier, N.,Cavarelli, J. (deposition date: 2021-09-29, release date: 2022-04-06, Last modification date: 2024-01-31)

Primary citation

Iannelli, G.,Milite, C.,Marechal, N.,Cura, V.,Bonnefond, L.,Troffer-Charlier, N.,Feoli, A.,Rescigno, D.,Wang, Y.,Cipriano, A.,Viviano, M.,Bedford, M.T.,Cavarelli, J.,Castellano, S.,Sbardella, G.
Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.
J.Med.Chem., 65:11574-11606, 2022

PubMed Abstract: Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.

PubMed: 35482954
DOI: 10.1021/acs.jmedchem.2c00252

Experimental method

X-RAY DIFFRACTION (2.19 Å)