5U4X

Coactivator-associated arginine methyltransferase 1 with TP-064

Summary for 5U4X

• Entry DOI: 10.2210/pdb5u4x/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, S-ADENOSYL-L-HOMOCYSTEINE, N-methyl-N-[(2-{1-[2-(methylamino)ethyl]piperidin-4-yl}pyridin-4-yl)methyl]-3-phenoxybenzamide, ... (5 entities in total)
• Functional Keywords: carm1, methyltransferase, tp-064, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: Q86X55
• Total number of polymer chains: 4
• Total formula weight: 158356.62

Authors

DONG, A.,ZENG, H.,Saikatendu, K.S.,STONE, H.,WALKER, J.R.,Seitova, A.,Hutchinson, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,BROWN, P.J.,WU, H.,Structural Genomics Consortium (SGC) (deposition date: 2016-12-06, release date: 2016-12-21, Last modification date: 2023-10-04)

Primary citation

Nakayama, K.,Szewczyk, M.M.,Dela Sena, C.,Wu, H.,Dong, A.,Zeng, H.,Li, F.,de Freitas, R.F.,Eram, M.S.,Schapira, M.,Baba, Y.,Kunitomo, M.,Cary, D.R.,Tawada, M.,Ohashi, A.,Imaeda, Y.,Saikatendu, K.S.,Grimshaw, C.E.,Vedadi, M.,Arrowsmith, C.H.,Barsyte-Lovejoy, D.,Kiba, A.,Tomita, D.,Brown, P.J.
TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma.
Oncotarget, 9:18480-18493, 2018

PubMed Abstract: Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC= 340 ± 30 nM) and Mediator complex subunit 12 (MED12; IC = 43 ± 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition.

PubMed: 29719619
DOI: 10.18632/oncotarget.24883

Experimental method

X-RAY DIFFRACTION (1.88 Å)