3u5k: Difference between revisions
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==Crystal Structure of the first bromodomain of human BRD4 in complex with Midazolam== | |||
<StructureSection load='3u5k' size='340' side='right' caption='[[3u5k]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3u5k]] is a 4 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=3U5K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3U5K FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=08J:8-CHLORO-6-(2-FLUOROPHENYL)-1-METHYL-4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE'>08J</scene></td></tr> | ||
[[http://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> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3u5j|3u5j]], [[3u5l|3u5l]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
==Function== | <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=3u5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u5k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3u5k RCSB], [http://www.ebi.ac.uk/pdbsum/3u5k PDBsum]</span></td></tr> | ||
</table> | |||
== Disease == | |||
[[http://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 == | |||
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | [[http://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 == | |||
Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure-activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors. | |||
Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family.,Filippakopoulos P, Picaud S, Fedorov O, Keller M, Wrobel M, Morgenstern O, Bracher F, Knapp S Bioorg Med Chem. 2011 Nov 4. PMID:22137933<ref>PMID:22137933</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Arrowsmith, C H | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra, C | [[Category: Bountra, C]] | ||
[[Category: Delft, F von | [[Category: Delft, F von]] | ||
[[Category: Edwards, A M | [[Category: Edwards, A M]] | ||
[[Category: Fedorov, O | [[Category: Fedorov, O]] | ||
[[Category: Felletar, I | [[Category: Felletar, I]] | ||
[[Category: Filippakopoulos, P | [[Category: Filippakopoulos, P]] | ||
[[Category: Knapp, S | [[Category: Knapp, S]] | ||
[[Category: Picaud, S | [[Category: Picaud, S]] | ||
[[Category: | [[Category: Structural genomic]] | ||
[[Category: Weigelt, J | [[Category: Weigelt, J]] | ||
[[Category: Brd4]] | [[Category: Brd4]] | ||
[[Category: Bromodomain containing protein 4]] | [[Category: Bromodomain containing protein 4]] | ||
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[[Category: Sgc]] | [[Category: Sgc]] | ||
[[Category: Signaling protein-inhibitor complex]] | [[Category: Signaling protein-inhibitor complex]] | ||