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5j47

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Revision as of 07:28, 10 June 2020

The X-ray structure of Inhibitor Bound to JCV Helicase

Structural highlights

5j47 is a 1 chain structure with sequence from Human polyomavirus (type jc). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5j40, 5j4v, 5j4y
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[LT_POVJC] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription (By similarity).

Publication Abstract from PubMed

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 muM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 muM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.,Bonafoux D, Nanthakumar S, Bandarage UK, Memmott C, Lowe D, Aronov AM, Bhisetti GR, Bonanno KC, Coll J, Leeman J, Lepre CA, Lu F, Perola E, Rijnbrand R, Taylor WP, Wilson D, Zhou Y, Zwahlen J, Ter Haar E J Med Chem. 2016 Jul 20. PMID:27385654^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bonafoux D, Nanthakumar S, Bandarage UK, Memmott C, Lowe D, Aronov AM, Bhisetti GR, Bonanno KC, Coll J, Leeman J, Lepre CA, Lu F, Perola E, Rijnbrand R, Taylor WP, Wilson D, Zhou Y, Zwahlen J, Ter Haar E. Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors. J Med Chem. 2016 Jul 20. PMID:27385654 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00486

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5j47"

@@ Line 1: / Line 1: @@
 ==The X-ray structure of Inhibitor Bound to JCV Helicase==
-<StructureSection load='5j47' size='340' side='right' caption='[[5j47]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
+<StructureSection load='5j47' size='340' side='right'caption='[[5j47]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j47]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J47 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J47 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j47]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_polyomavirus_(type_jc) Human polyomavirus (type jc)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J47 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J47 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6JJ:6-(2-PHENOXYPHENYL)[1,2,4]TRIAZOLO[3,4-B][1,3,4]THIADIAZOLE'>6JJ</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6JJ:6-(2-PHENOXYPHENYL)[1,2,4]TRIAZOLO[3,4-B][1,3,4]THIADIAZOLE'>6JJ</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5j40|5j40]], [[5j4v|5j4v]], [[5j4y|5j4y]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j47 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j47 OCA], [http://pdbe.org/5j47 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j47 RCSB], [http://www.ebi.ac.uk/pdbsum/5j47 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j47 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5j47 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j47 OCA], [http://pdbe.org/5j47 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j47 RCSB], [http://www.ebi.ac.uk/pdbsum/5j47 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j47 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5j47" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Large T Antigen|Large T Antigen]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Haar, E Ter]]
 [[Category: Atp]]

5j47

From Proteopedia

Revision as of 07:28, 10 June 2020

The X-ray structure of Inhibitor Bound to JCV Helicase

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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