6mau

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<StructureSection load='6mau' size='340' side='right'caption='[[6mau]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
<StructureSection load='6mau' size='340' side='right'caption='[[6mau]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6mau]] is a 1 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=6MAU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MAU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6mau]] 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=6MAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MAU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JBS:1-(4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-[(3S)-3-phenylmorpholin-4-yl]quinazolin-2-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol'>JBS</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JBS:1-(4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-[(3S)-3-phenylmorpholin-4-yl]quinazolin-2-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol'>JBS</scene></td></tr>
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<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=6mau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mau OCA], [http://pdbe.org/6mau PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mau RCSB], [http://www.ebi.ac.uk/pdbsum/6mau PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mau ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mau OCA], [https://pdbe.org/6mau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mau RCSB], [https://www.ebi.ac.uk/pdbsum/6mau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mau ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.
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Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases.,Yang SM, Yoshioka M, Strovel JW, Urban DJ, Hu X, Hall MD, Jadhav A, Maloney DJ Bioorg Med Chem Lett. 2019 Mar 12. pii: S0960-894X(19)30143-X. doi:, 10.1016/j.bmcl.2019.03.014. PMID:30905542<ref>PMID:30905542</ref>
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==See Also==
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*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6mau" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chan, S G]]
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[[Category: Chan SG]]
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[[Category: Connors, C R]]
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[[Category: Connors CR]]
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[[Category: Fontano, E]]
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[[Category: Fontano E]]
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[[Category: Lakshminarasimhan, D]]
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[[Category: Lakshminarasimhan D]]
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[[Category: Nadupalli, A]]
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[[Category: Nadupalli A]]
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[[Category: Olland, A M]]
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[[Category: Olland AM]]
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[[Category: Suto, R K]]
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[[Category: Suto RK]]
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[[Category: White, A]]
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[[Category: White A]]
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[[Category: Protein binding]]
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Current revision

Crystal structure of human BRD4(1) in complex with CN210 (compound 19)

PDB ID 6mau

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