4IKP

Crystal structure of coactivator-associated arginine methyltransferase 1 with methylenesinefungin

Summary for 4IKP

• Entry DOI: 10.2210/pdb4ikp/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, (2S,5S)-2,6-diamino-5-{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl}hexanoic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: 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: 157026.72

Authors

Dong, A.,Dombrovski, L.,He, H.,Ibanez, G.,Wernimont, A.,Zheng, W.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Min, J.,Luo, M.,Wu, H.,Structural Genomics Consortium (SGC) (deposition date: 2012-12-27, release date: 2013-02-13, Last modification date: 2023-09-20)

Primary citation

Cai, X.C.,Zhang, T.,Kim, E.J.,Jiang, M.,Wang, K.,Wang, J.,Chen, S.,Zhang, N.,Wu, H.,Li, F.,Dela Sena, C.C.,Zeng, H.,Vivcharuk, V.,Niu, X.,Zheng, W.,Lee, J.P.,Chen, Y.,Barsyte, D.,Szewczyk, M.,Hajian, T.,Ibanez, G.,Dong, A.,Dombrovski, L.,Zhang, Z.,Deng, H.,Min, J.,Arrowsmith, C.H.,Mazutis, L.,Shi, L.,Vedadi, M.,Brown, P.J.,Xiang, J.,Qin, L.X.,Xu, W.,Luo, M.
A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.
Elife, 8:-, 2019

PubMed Abstract: CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here ( in this work) is presented as a CARM1 chemical probe with pro-drug properties. () can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of , and on-target engagement. () recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the ()-associated reduction of invasiveness acts by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, () and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

PubMed: 31657716
DOI: 10.7554/eLife.47110

Experimental method

X-RAY DIFFRACTION (2 Å)