8T1Q

Crystal structure of human CPSF73 catalytic segment in complex with compound 1

8T1Q の概要

• エントリーDOI: 10.2210/pdb8t1q/pdb
• 分子名称: Cleavage and polyadenylation specificity factor subunit 3, 3-[7,7-bis(oxidanyl)-8-oxa-7-boranuidabicyclo[4.3.0]nona-1,3,5-trien-5-yl]-~{N}-[3-(4-ethanoylphenyl)phenyl]propanamide, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: nuclease, complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55169.18

構造登録者

Huang, J.,Tong, L. (登録日: 2023-06-02, 公開日: 2023-11-08, 最終更新日: 2024-01-31)

主引用文献

Tao, Y.,Budhipramono, A.,Huang, J.,Fang, M.,Xie, S.,Kim, J.,Khivansara, V.,Dominski, Z.,Tong, L.,De Brabander, J.K.,Nijhawan, D.
Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3.
Cell Chem Biol, 31:139-, 2024

PubMed Abstract: A novel class of benzoxaboroles was reported to induce cancer cell death but the mechanism was unknown. Using a forward genetics platform, we discovered mutations in cleavage and polyadenylation specific factor 3 (CPSF3) that reduce benzoxaborole binding and confer resistance. CPSF3 is the endonuclease responsible for pre-mRNA 3'-end processing, which is also important for RNA polymerase II transcription termination. Benzoxaboroles inhibit this endonuclease activity of CPSF3 in vitro and also curb transcriptional termination in cells, which results in the downregulation of numerous constitutively expressed genes. Furthermore, we used X-ray crystallography to demonstrate that benzoxaboroles bind to the active site of CPSF3 in a manner distinct from the other known inhibitors of CPSF3. The benzoxaborole compound impeded the growth of cancer cell lines derived from different lineages. Our results suggest benzoxaboroles may represent a promising lead as CPSF3 inhibitors for clinical development.

PubMed: 37967558
DOI: 10.1016/j.chembiol.2023.10.019

実験手法

X-RAY DIFFRACTION (1.7 Å)