7E4W

Human Transcriptional Co-activator PC4 (C-terminal Domain) in space group P1211

7E4W の概要

• エントリーDOI: 10.2210/pdb7e4w/pdb
• 分子名称: Activated RNA polymerase II transcriptional coactivator p15 (2 entities in total)
• 機能のキーワード: human transcriptional coactivator pc4, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 124544.38

構造登録者

Dev, A.,Pandey, B.,Basu, G. (登録日: 2021-02-15, 公開日: 2021-09-22, 最終更新日: 2023-11-29)

主引用文献

Pandey, B.,Dev, A.,Chakravorty, D.,Bhandare, V.V.,Polley, S.,Roy, S.,Basu, G.
Insights on the disruption of the complex between human positive coactivator 4 and p53 by small molecules.
Biochem.Biophys.Res.Commun., 578:15-20, 2021

PubMed Abstract: Interaction between human positive coactivator 4 (PC4), an abundant nuclear protein, and the tumor suppressor protein p53 plays a crucial role in initiating apoptosis. In certain neurodegenerative diseases PC4 assisted-p53-dependent apoptosis may play a central role. Thus, disruption of p53-PC4 interaction may be a good drug target for certain disease pathologies. A p53-derived short peptide (AcPep) that binds the C-terminal domain of PC4 (C-PC4) is known to disrupt PC4-p53 interaction. To fully characterize its binding mode and binding site on PC4, we co-crystallized C-PC4 with the peptide and determined its structure. The crystal, despite exhibiting mass spectrometric signature of the peptide, lacked peptide electron density and showed a novel crystal lattice, when compared to C-PC4 crystals without the peptide. Using peptide-docked models of crystal lattices, corresponding to our structure and the peptide-devoid structure we show the origin of the novel crystal lattice to be dynamically bound peptide at the previously identified putative binding site. The weak binding is proposed to be due to the lack of the N-terminal domain of PC4 (N-PC4), which we experimentally show to be disordered with no effect on PC4 stability. Taking cue from the structure, virtual screening of ∼18.6 million small molecules from the ZINC15 database was performed, followed by toxicity and binding free energy filtering. The novel crystal lattice of C-PC4 in presence of the peptide, the role of the disordered N-PC4 and the high throughput identification of potent small molecules will allow a better understanding and control of p53-PC4 interaction.

PubMed: 34534740
DOI: 10.1016/j.bbrc.2021.09.020

実験手法

X-RAY DIFFRACTION (2.9 Å)