6D2L

Crystal structure of human CARM1 with (S)-SKI-72

6D2L の概要

• エントリーDOI: 10.2210/pdb6d2l/pdb
• 分子名称: Histone-arginine methyltransferase CARM1, (2S,5S)-2-amino-6-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-5-[(benzylamino)methyl]-N-[2-(4-hydroxyphenyl)ethyl]hexanamide, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: carm1, prmt4, ski-72 inhibitor, structural genomics, structural genomics consortium, sgc, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: Q86X55
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 237959.30

構造登録者

DONG, A.,ZENG, H.,WALKER, J.R.,Hutchinson, A.,Seitova, A.,LUO, M.,CAI, X.C.,KE, W.,WANG, J.,SHI, C.,ZHENG, W.,LEE, J.P.,IBANEZ, G.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,BROWN, P.J.,WU, H.,Structural Genomics Consortium (SGC) (登録日: 2018-04-13, 公開日: 2018-05-23, 最終更新日: 2023-08-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)