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5dlx

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FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-{3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}piperidine-4-carboxamide

Structural highlights

5dlx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse 'PPI-like' modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using Homogeneous Time-Resolved Fluorescence (HTRF(R)) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with non-oriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets.

Protein-protein interaction inhibition (2P2I)-oriented chemical library accelerates hit discovery.,Milhas S, Raux B, Betzi S, Derviaux C, Roche P, Restouin A, Basse MJ, Rebuffet E, Lugari A, Badol M, Kashyap R, Lissitzky JC, Eydoux C, Hamon V, Gourdel ME, Combes S, Zimmermann P, Aurrand-Lions M, Roux T, Rogers C, Muller S, Knapp S, Trinquet E, Collette Y, Guillemot JC, Morelli X ACS Chem Biol. 2016 May 24. PMID:27219844^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Milhas S, Raux B, Betzi S, Derviaux C, Roche P, Restouin A, Basse MJ, Rebuffet E, Lugari A, Badol M, Kashyap R, Lissitzky JC, Eydoux C, Hamon V, Gourdel ME, Combes S, Zimmermann P, Aurrand-Lions M, Roux T, Rogers C, Muller S, Knapp S, Trinquet E, Collette Y, Guillemot JC, Morelli X. Protein-protein interaction inhibition (2P2I)-oriented chemical library accelerates hit discovery. ACS Chem Biol. 2016 May 24. PMID:27219844 doi:http://dx.doi.org/10.1021/acschembio.6b00286

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5dlx"

@@ Line 1: / Line 1: @@
 ==FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-{3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}piperidine-4-carboxamide==
-<StructureSection load='5dlx' size='340' side='right' caption='[[5dlx]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='5dlx' size='340' side='right'caption='[[5dlx]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5dlx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DLX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DLX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5dlx]] 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=5DLX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DLX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5D2:N-{3-[4-(3-CHLOROPHENYL)PIPERAZIN-1-YL]PROPYL}-1-(3-METHYL[1,2,4]TRIAZOLO[4,3-B]PYRIDAZIN-6-YL)PIPERIDINE-4-CARBOXAMIDE'>5D2</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]] 1.9&#8491;</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=5dlx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dlx OCA], [http://pdbe.org/5dlx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dlx RCSB], [http://www.ebi.ac.uk/pdbsum/5dlx PDBsum]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5D2:N-{3-[4-(3-CHLOROPHENYL)PIPERAZIN-1-YL]PROPYL}-1-(3-METHYL[1,2,4]TRIAZOLO[4,3-B]PYRIDAZIN-6-YL)PIPERIDINE-4-CARBOXAMIDE'>5D2</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=5dlx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dlx OCA], [https://pdbe.org/5dlx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dlx RCSB], [https://www.ebi.ac.uk/pdbsum/5dlx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dlx ProSAT]</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>
+[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 ==
-[[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;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5dlx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Betzi, S]]
+[[Category: Homo sapiens]]
-[[Category: Morelli, X]]
+[[Category: Large Structures]]
-[[Category: Raux, B]]
+[[Category: Betzi S]]
-[[Category: Rebuffet, E]]
+[[Category: Morelli X]]
-[[Category: Brd4]]
+[[Category: Raux B]]
-[[Category: Brd4_bd1]]
+[[Category: Rebuffet E]]
-[[Category: Bromodomain]]
-[[Category: Epigenetic reader]]
-[[Category: Histone]]
-[[Category: Inhibitor]]
-[[Category: Transcription]]

5dlx

From Proteopedia

Current revision

FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-{3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}piperidine-4-carboxamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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