6M8Q

Cleavage and Polyadenylation Specificity Factor Subunit 3 (CPSF3) in complex with NVP-LTM531

6M8Q の概要

• エントリーDOI: 10.2210/pdb6m8q/pdb
• 分子名称: Cleavage and polyadenylation specificity factor subunit 3, ZINC ION, N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzene-1-carbonyl}-L-phenylalanine, ... (5 entities in total)
• 機能のキーワード: polyadenylation, metallo-b-lactamase, pre-mrna processing, artemis, v(d)j recombination, double-strand break repair, hydrolase, rna binding protein, hydroxylase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110225.46

構造登録者

Weihofen, W.A.,Salcius, M.,Michaud, G. (登録日: 2018-08-22, 公開日: 2019-11-27, 最終更新日: 2023-10-11)

主引用文献

Ross, N.T.,Lohmann, F.,Carbonneau, S.,Fazal, A.,Weihofen, W.A.,Gleim, S.,Salcius, M.,Sigoillot, F.,Henault, M.,Carl, S.H.,Rodriguez-Molina, J.B.,Miller, H.R.,Brittain, S.M.,Murphy, J.,Zambrowski, M.,Boynton, G.,Wang, Y.,Chen, A.,Molind, G.J.,Wilbertz, J.H.,Artus-Revel, C.G.,Jia, M.,Akinjiyan, F.A.,Turner, J.,Knehr, J.,Carbone, W.,Schuierer, S.,Reece-Hoyes, J.S.,Xie, K.,Saran, C.,Williams, E.T.,Roma, G.,Spencer, M.,Jenkins, J.,George, E.L.,Thomas, J.R.,Michaud, G.,Schirle, M.,Tallarico, J.,Passmore, L.A.,Chao, J.A.,Beckwith, R.E.J.
CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.
Nat.Chem.Biol., 16:50-59, 2020

PubMed Abstract: The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

PubMed: 31819276
DOI: 10.1038/s41589-019-0424-1

実験手法

X-RAY DIFFRACTION (2.49 Å)