7e4w | pdb_00007e4w
Human Transcriptional Co-activator PC4 (C-terminal Domain) in space group P1211
Structural highlights
FunctionTCP4_HUMAN General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. May be involved in stabilizing the multiprotein transcription complex. Binds single-stranded DNA. Also binds, in vitro, non-specifically to double-stranded DNA (ds DNA).[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedInteraction 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 approximately 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. Insights on the disruption of the complex between human positive coactivator 4 and p53 by small molecules.,Pandey B, Dev A, Chakravorty D, Bhandare VV, Polley S, Roy S, Basu G Biochem Biophys Res Commun. 2021 Nov 12;578:15-20. doi:, 10.1016/j.bbrc.2021.09.020. Epub 2021 Sep 10. PMID:34534740[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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