7mce
From Proteopedia
(Difference between revisions)
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==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol== | ==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol== | ||
| - | <StructureSection load='7mce' size='340' side='right'caption='[[7mce]]' scene=''> | + | <StructureSection load='7mce' size='340' side='right'caption='[[7mce]], [[Resolution|resolution]] 1.76Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MCE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7mce]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MCE FirstGlance]. <br> |
| - | </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=7mce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mce OCA], [https://pdbe.org/7mce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mce RCSB], [https://www.ebi.ac.uk/pdbsum/7mce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mce ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YWY:2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol'>YWY</scene></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=7mce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mce OCA], [https://pdbe.org/7mce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mce RCSB], [https://www.ebi.ac.uk/pdbsum/7mce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mce ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-((2)H3)methyl-1- methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10. | ||
| + | |||
| + | Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.,Hill MD, Quesnelle C, Tokarski J, Fang H, Fanslau C, Haarhoff Z, Kramer M, Madari S, Wiebesiek A, Morrison J, Simmermacher-Mayer J, Sinz M, Westhouse R, Xie C, Zhao J, Huang L, Sheriff S, Yan C, Marsilio F, Everlof G, Zvyaga T, Lee F, Gavai AV, Degnan AP Bioorg Med Chem Lett. 2021 Sep 21;51:128376. doi: 10.1016/j.bmcl.2021.128376. PMID:34560263<ref>PMID:34560263</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7mce" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Sheriff S]] | + | [[Category: Sheriff, S]] |
| + | [[Category: Brd4]] | ||
| + | [[Category: Bromodomain containing protein 4]] | ||
| + | [[Category: Bromodomain-containing protein 4 isoform long]] | ||
| + | [[Category: Cap]] | ||
| + | [[Category: Cell cycle]] | ||
| + | [[Category: Hunk1]] | ||
| + | [[Category: Mcap]] | ||
| + | [[Category: Mitotic chromosome associated protein sgc]] | ||
Revision as of 05:54, 6 October 2021
CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol
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