4cfl

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N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH LY303511

Structural highlights

4cfl 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 1.32Å
Ligands:8DQ, EDO, GOL
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

A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.

The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains.,Dittmann A, Werner T, Chung CW, Savitski MM, Falth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK, Bantscheff M, Drewes G ACS Chem Biol. 2014 Feb 21;9(2):495-502. doi: 10.1021/cb400789e. Epub 2013 Dec, 10. PMID:24533473[3]

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

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Citations
21 reviews cite this structure
Targeting bromodomains: epigenetic readers of lysine acetylation.
Filippakopoulos et al. (2014)
20 more
32 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Dittmann A, Werner T, Chung CW, Savitski MM, Falth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK, Bantscheff M, Drewes G. The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains. ACS Chem Biol. 2014 Feb 21;9(2):495-502. doi: 10.1021/cb400789e. Epub 2013 Dec, 10. PMID:24533473 doi:http://dx.doi.org/10.1021/cb400789e

Contents


PDB ID 4cfl

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