7mls: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==X-ray crystal structure of human BRD4(D1) in complex with 2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine (compound 23)== | ==X-ray crystal structure of human BRD4(D1) in complex with 2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine (compound 23)== | ||
<StructureSection load='7mls' size='340' side='right'caption='[[7mls]]' scene=''> | <StructureSection load='7mls' size='340' side='right'caption='[[7mls]], [[Resolution|resolution]] 1.26Å' 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=7MLS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MLS FirstGlance]. <br> | <table><tr><td colspan='2'>[[7mls]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MLS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MLS 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=7mls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mls OCA], [https://pdbe.org/7mls PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mls RCSB], [https://www.ebi.ac.uk/pdbsum/7mls PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mls 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZHM:2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine'>ZHM</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([https://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=7mls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mls OCA], [https://pdbe.org/7mls PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mls RCSB], [https://www.ebi.ac.uk/pdbsum/7mls PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mls 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 == | |||
The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable N-acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1 Kd of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-alpha-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins. | |||
4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.,Cui H, Carlson AS, Schleiff MA, Divakaran A, Johnson JA, Buchholz CR, Zahid H, Vail NR, Shi K, Aihara H, Harki DA, Miller GP, Topczewski JJ, Pomerantz WCK J Med Chem. 2021 Jul 22;64(14):10497-10511. doi: 10.1021/acs.jmedchem.1c00933., Epub 2021 Jul 8. PMID:34236185<ref>PMID:34236185</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7mls" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Aihara H]] | [[Category: Aihara, H]] | ||
[[Category: Buchholz | [[Category: Buchholz, C R]] | ||
[[Category: Cui H]] | [[Category: Cui, H]] | ||
[[Category: Johnson | [[Category: Johnson, J A]] | ||
[[Category: Pomerantz | [[Category: Pomerantz, W C.K]] | ||
[[Category: Shi K]] | [[Category: Shi, K]] | ||
[[Category: Zahid H]] | [[Category: Zahid, H]] | ||
[[Category: Brd4]] | |||
[[Category: Gene regulation]] | |||
[[Category: Gene regulation-inhibitor complex]] | |||
Revision as of 13:36, 4 August 2021
X-ray crystal structure of human BRD4(D1) in complex with 2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine (compound 23)X-ray crystal structure of human BRD4(D1) in complex with 2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine (compound 23)
Structural highlights
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 PubMedThe bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable N-acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1 Kd of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-alpha-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins. 4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.,Cui H, Carlson AS, Schleiff MA, Divakaran A, Johnson JA, Buchholz CR, Zahid H, Vail NR, Shi K, Aihara H, Harki DA, Miller GP, Topczewski JJ, Pomerantz WCK J Med Chem. 2021 Jul 22;64(14):10497-10511. doi: 10.1021/acs.jmedchem.1c00933., Epub 2021 Jul 8. PMID:34236185[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||