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| ==Crystal Structure of the first bromodomain of human BRD4 in complex with Midazolam== | | ==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=''> | | <StructureSection load='3u5k' size='340' side='right'caption='[[3u5k]], [[Resolution|resolution]] 1.80Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3u5k]] 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=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> | | <table><tr><td colspan='2'>[[3u5k]] is a 4 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=3U5K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U5K FirstGlance]. <br> |
| </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> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3u5j|3u5j]], [[3u5l|3u5l]]</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=08J:8-CHLORO-6-(2-FLUOROPHENYL)-1-METHYL-4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE'>08J</scene></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 HUMAN])</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=3u5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u5k OCA], [https://pdbe.org/3u5k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3u5k RCSB], [https://www.ebi.ac.uk/pdbsum/3u5k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3u5k ProSAT]</span></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=3u5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u5k OCA], [http://pdbe.org/3u5k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3u5k RCSB], [http://www.ebi.ac.uk/pdbsum/3u5k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3u5k ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease == | | == 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> | | [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 == | | == Function == |
| [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | | [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;">
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| == Publication Abstract from PubMed ==
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| 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.
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| 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>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 3u5k" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Bromodomain-containing protein|Bromodomain-containing protein]] | | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Human]] | | [[Category: Homo sapiens]] |
| [[Category: Arrowsmith, C H]] | | [[Category: Large Structures]] |
| [[Category: Bountra, C]] | | [[Category: Arrowsmith CH]] |
| [[Category: Delft, F von]] | | [[Category: Bountra C]] |
| [[Category: Edwards, A M]] | | [[Category: Edwards AM]] |
| [[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: Structural genomic]]
| | [[Category: Weigelt J]] |
| [[Category: Weigelt, J]] | | [[Category: Von Delft F]] |
| [[Category: Brd4]] | |
| [[Category: Bromodomain containing protein 4]]
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| [[Category: Bromodomain-containing protein 4 isoform long]]
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| [[Category: Cap]]
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| [[Category: Hunk1]]
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| [[Category: Mcap]]
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| [[Category: Mitotic chromosome associated protein]]
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| [[Category: Sgc]]
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| [[Category: Signaling protein-inhibitor complex]]
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