8q34: Difference between revisions
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==Crystal structure of the first bromodomain of human BRD4 in complex with the ligand ZZ001229a== | ==Crystal structure of the first bromodomain of human BRD4 in complex with the ligand ZZ001229a== | ||
<StructureSection load='8q34' size='340' side='right'caption='[[8q34]]' scene=''> | <StructureSection load='8q34' size='340' side='right'caption='[[8q34]], [[Resolution|resolution]] 1.48Å' 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=8Q34 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Q34 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8q34]] 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=8Q34 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Q34 FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction</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]] 1.48Å</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=8q34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8q34 OCA], [https://pdbe.org/8q34 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8q34 RCSB], [https://www.ebi.ac.uk/pdbsum/8q34 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8q34 ProSAT]</span></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=8q34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8q34 OCA], [https://pdbe.org/8q34 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8q34 RCSB], [https://www.ebi.ac.uk/pdbsum/8q34 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8q34 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 == | |||
Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas(G12D) protein, and the yet unliganded N-terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. | |||
Mapping protein binding sites by photoreactive fragment pharmacophores.,Abranyi-Balogh P, Bajusz D, Orgovan Z, Keeley AB, Petri L, Peczka N, Szalai TV, Palfy G, Gadanecz M, Grant EK, Imre T, Takacs T, Randelovic I, Baranyi M, Marton A, Schlosser G, Ashraf QF, de Araujo ED, Karancsi T, Buday L, Tovari J, Perczel A, Bush JT, Keseru GM Commun Chem. 2024 Jul 31;7(1):168. doi: 10.1038/s42004-024-01252-w. PMID:39085342<ref>PMID:39085342</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8q34" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: MacLean | [[Category: Abranyi-Balogh P]] | ||
[[Category: Bajusz D]] | |||
[[Category: Balcomb BH]] | |||
[[Category: Gao Q]] | |||
[[Category: Keeley A]] | |||
[[Category: Keseru GM]] | |||
[[Category: Koekemoer L]] | |||
[[Category: MacLean EM]] | |||
[[Category: Williams E]] | |||
[[Category: Von Delft F]] | |||