Structural highlights
4a9m is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , |
| Related: | 2yek, 4a9e, 1x0j, 4a9f, 2ydw, 4a9j, 4a9i |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1]
Publication Abstract from PubMed
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.
Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides.,Bamborough P, Diallo H, Goodacre JD, Gordon L, Lewis A, Seal JT, Wilson DM, Woodrow MD, Chung CW J Med Chem. 2012 Jan 26;55(2):587-96. Epub 2012 Jan 11. PMID:22136469[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018
- ↑ Bamborough P, Diallo H, Goodacre JD, Gordon L, Lewis A, Seal JT, Wilson DM, Woodrow MD, Chung CW. Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J Med Chem. 2012 Jan 26;55(2):587-96. Epub 2012 Jan 11. PMID:22136469 doi:10.1021/jm201283q
