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7e4w

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

Structural highlights

7e4w is a 16 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TCP4_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 PubMed

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 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

↑ Kretzschmar M, Kaiser K, Lottspeich F, Meisterernst M. A novel mediator of class II gene transcription with homology to viral immediate-early transcriptional regulators. Cell. 1994 Aug 12;78(3):525-34. PMID:8062392
↑ Ge H, Roeder RG. Purification, cloning, and characterization of a human coactivator, PC4, that mediates transcriptional activation of class II genes. Cell. 1994 Aug 12;78(3):513-23. PMID:8062391
↑ Kaiser K, Stelzer G, Meisterernst M. The coactivator p15 (PC4) initiates transcriptional activation during TFIIA-TFIID-promoter complex formation. EMBO J. 1995 Jul 17;14(14):3520-7. PMID:7628453
↑ Malik S, Guermah M, Roeder RG. A dynamic model for PC4 coactivator function in RNA polymerase II transcription. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2192-7. PMID:9482861
↑ Jonker HR, Wechselberger RW, Pinkse M, Kaptein R, Folkers GE. Gradual phosphorylation regulates PC4 coactivator function. FEBS J. 2006 Apr;273(7):1430-44. PMID:16689930 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05165.x
↑ Brandsen J, Werten S, van der Vliet PC, Meisterernst M, Kroon J, Gros P. C-terminal domain of transcription cofactor PC4 reveals dimeric ssDNA binding site. Nat Struct Biol. 1997 Nov;4(11):900-3. PMID:9360603
↑ Jonker HR, Wechselberger RW, Boelens R, Kaptein R, Folkers GE. The intrinsically unstructured domain of PC4 modulates the activity of the structured core through inter- and intramolecular interactions. Biochemistry. 2006 Apr 18;45(15):5067-81. PMID:16605275 doi:http://dx.doi.org/10.1021/bi052531b
↑ Pandey B, Dev A, Chakravorty D, Bhandare VV, 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. 2021 Nov 12;578:15-20. doi:, 10.1016/j.bbrc.2021.09.020. Epub 2021 Sep 10. PMID:34534740 doi:http://dx.doi.org/10.1016/j.bbrc.2021.09.020

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7e4w"

Categories: Homo sapiens | Large Structures | Basu G | Dev A | Pandey B

@@ Line 3: / Line 3: @@
 <StructureSection load='7e4w' size='340' side='right'caption='[[7e4w]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7e4w]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E4W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E4W FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7e4w]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E4W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E4W FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e4w OCA], [https://pdbe.org/7e4w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e4w RCSB], [https://www.ebi.ac.uk/pdbsum/7e4w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e4w ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e4w OCA], [https://pdbe.org/7e4w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e4w RCSB], [https://www.ebi.ac.uk/pdbsum/7e4w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e4w ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/TCP4_HUMAN TCP4_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).<ref>PMID:8062392</ref> <ref>PMID:8062391</ref> <ref>PMID:7628453</ref> <ref>PMID:9482861</ref> <ref>PMID:16689930</ref> <ref>PMID:9360603</ref> <ref>PMID:16605275</ref>
+[https://www.uniprot.org/uniprot/TCP4_HUMAN TCP4_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).<ref>PMID:8062392</ref> <ref>PMID:8062391</ref> <ref>PMID:7628453</ref> <ref>PMID:9482861</ref> <ref>PMID:16689930</ref> <ref>PMID:9360603</ref> <ref>PMID:16605275</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Basu, G]]
+[[Category: Basu G]]
-[[Category: Dev, A]]
+[[Category: Dev A]]
-[[Category: Pandey, B]]
+[[Category: Pandey B]]
-[[Category: Human transcriptional coactivator pc4]]
-[[Category: Transcription]]

7e4w

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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