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5h1u

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Revision as of 12:44, 6 November 2017

Complex structure of TRIM24 PHD-bromodomain and inhibitor 2

Structural highlights

5h1u is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5h1t, 5h1v
Gene:	TRIM24, RNF82, TIF1, TIF1A (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TIF1A_HUMAN] Defects in TRIM24 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=A chromosomal aberration involving TRIM24/TIF1 is found in thyroid papillary carcinomas. Translocation t(7;10)(q32;q11) with RET. The translocation generates the TRIM24/RET (PTC6) oncogene.

Function

[TIF1A_HUMAN] Transcriptional coactivator that interacts with numerous nuclear receptors and coactivators and modulates the transcription of target genes. Interacts with chromatin depending on histone H3 modifications, having the highest affinity for histone H3 that is both unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-23' (H3K23ac). Has E3 protein-ubiquitin ligase activity. Promotes ubiquitination and proteasomal degradation of p53/TP53. Plays a role in the regulation of cell proliferation and apoptosis, at least in part via its effects on p53/TP53 levels. Up-regulates ligand-dependent transcription activation by AR, GCR/NR3C1, thyroid hormone receptor (TR) and ESR1. Modulates transcription activation by retinoic acid (RA) receptors, including RARA. Plays a role in regulating retinoic acid-dependent proliferation of hepatocytes (By similarity).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors. Interestingly, the polar substitution on the warhead of one new inhibitor pulls the whole ligand approximately 2 A into the inner side pocket of the TRIM24 bromodomain, and thus exhibits a binding mode significantly different from other known bromodomain ligands. This mode provides a useful handle for further hit-to-lead evolution towards novel inhibitors of the TRIM24 bromodomain. This article is protected by copyright. All rights reserved.

The Polar Warhead of a TRIM24 Bromodomain Inhibitor Rearranges a Water-Mediated Interaction Network.,Liu J, Li F, Bao H, Jiang Y, Zhang S, Ma R, Gao J, Wu J, Ruan K FEBS J. 2017 Feb 16. doi: 10.1111/febs.14041. PMID:28207202^[4]

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

References

↑ Teyssier C, Ou CY, Khetchoumian K, Losson R, Stallcup MR. Transcriptional intermediary factor 1alpha mediates physical interaction and functional synergy between the coactivator-associated arginine methyltransferase 1 and glucocorticoid receptor-interacting protein 1 nuclear receptor coactivators. Mol Endocrinol. 2006 Jun;20(6):1276-86. Epub 2005 Dec 1. PMID:16322096 doi:10.1210/me.2005-0393
↑ Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC. Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11612-6. doi:, 10.1073/pnas.0813177106. Epub 2009 Jun 25. PMID:19556538 doi:10.1073/pnas.0813177106
↑ Tsai WW, Wang Z, Yiu TT, Akdemir KC, Xia W, Winter S, Tsai CY, Shi X, Schwarzer D, Plunkett W, Aronow B, Gozani O, Fischle W, Hung MC, Patel DJ, Barton MC. TRIM24 links a non-canonical histone signature to breast cancer. Nature. 2010 Dec 16;468(7326):927-32. PMID:21164480 doi:10.1038/nature09542
↑ Liu J, Li F, Bao H, Jiang Y, Zhang S, Ma R, Gao J, Wu J, Ruan K. The Polar Warhead of a TRIM24 Bromodomain Inhibitor Rearranges a Water-Mediated Interaction Network. FEBS J. 2017 Feb 16. doi: 10.1111/febs.14041. PMID:28207202 doi:http://dx.doi.org/10.1111/febs.14041

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5h1u"

Categories: Human | Liu, J | Transcription transcription inhibitor | Transcription-transcription inhibitor complex

@@ Line 3: / Line 3: @@
 <StructureSection load='5h1u' size='340' side='right' caption='[[5h1u]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5h1u]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5H1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5H1U FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5h1u]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5H1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5H1U FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6KT:2-AMINO-1,3-BENZOTHIAZOLE-6-CARBOXAMIDE'>6KT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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">[[5h1t|5h1t]], [[5h1v|5h1v]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRIM24, RNF82, TIF1, TIF1A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5h1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h1u OCA], [http://pdbe.org/5h1u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5h1u RCSB], [http://www.ebi.ac.uk/pdbsum/5h1u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5h1u ProSAT]</span></td></tr>
 </table>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Liu, J]]
 [[Category: Transcription transcription inhibitor]]
 [[Category: Transcription-transcription inhibitor complex]]

5h1u

From Proteopedia

Revision as of 12:44, 6 November 2017

Complex structure of TRIM24 PHD-bromodomain and inhibitor 2

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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