3p5o

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor

Structural highlights

3p5o is a 1 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 1.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

Suppression of inflammation by a synthetic histone mimic.,Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A Nature. 2010 Dec 23;468(7327):1119-23. Epub 2010 Nov 10. PMID:21068722^[3]

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

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. Suppression of inflammation by a synthetic histone mimic. Nature. 2010 Dec 23;468(7327):1119-23. Epub 2010 Nov 10. PMID:21068722 doi:10.1038/nature09589

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3p5o"

Categories: Homo sapiens | Large Structures | Chung C

@@ Line 1: / Line 1: @@
-[[Image:3p5o.png|left|200px]]
-<!--
+==Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor==
-The line below this paragraph, containing "STRUCTURE_3p5o", creates the "Structure Box" on the page.
+<StructureSection load='3p5o' size='340' side='right'caption='[[3p5o]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3p5o]] is a 1 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=3P5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3P5O FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EAM:2-[(4S)-6-(4-CHLOROPHENYL)-8-METHOXY-1-METHYL-4H-[1,2,4]TRIAZOLO[4,3-A][1,4]BENZODIAZEPIN-4-YL]-N-ETHYLACETAMIDE'>EAM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-{{STRUCTURE_3p5o|  PDB=3p5o  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3p5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3p5o OCA], [https://pdbe.org/3p5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3p5o RCSB], [https://www.ebi.ac.uk/pdbsum/3p5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3p5o ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
-===Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor===
+Suppression of inflammation by a synthetic histone mimic.,Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A Nature. 2010 Dec 23;468(7327):1119-23. Epub 2010 Nov 10. PMID:21068722<ref>PMID:21068722</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3p5o" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_21068722}}, adds the Publication Abstract to the page
+*[[Bromodomain-containing protein|Bromodomain-containing protein]]
-(as it appears on PubMed at http://www.pubmed.gov), where 21068722 is the PubMed ID number.
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
--->
+== References ==
-{{ABSTRACT_PUBMED_21068722}}
+<references/>
+__TOC__
-==About this Structure==
+</StructureSection>
-[[3p5o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3P5O OCA].
-==Reference==
-<ref group="xtra">PMID:21068722</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Chung, C.]]
+[[Category: Large Structures]]
-[[Category: Antagonist]]
+[[Category: Chung C]]
-[[Category: Brd4]]
-[[Category: Bromodomain containing protein 4]]
-[[Category: Ibet]]
-[[Category: Inhibition of acetylated lysine histone binding]]
-[[Category: Signaling protein-inhibitor complex]]
-[[Category: Transcription regulator]]

3p5o

From Proteopedia

Current revision

Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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