6wgx

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Cocrystal of BRD4(D1) with a selective inhibitor

Structural highlights

6wgx is a 2 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 1.53Å
Ligands:EDO, U0D
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

Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to of BRD4 D1. In competitive inhibition assays we show that our lead compound is 9-33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions.

Selective N-terminal BRD4 bromodomain inhibitors by targeting non-conserved residues and structured water displacement.,Pomerantz WCK, Cui H, Divakaran A, Pandey AK, Johnson JA, Zahid H, Hoell ZJ, Ellingson MO, Shi K, Aihara H, Harki DA Angew Chem Int Ed Engl. 2020 Sep 24. doi: 10.1002/anie.202008625. PMID:32975004[3]

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

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Citations
5 reviews cite this structure
Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.
Tang et al. (2021)
4 more
9 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. ↑ Pomerantz WCK, Cui H, Divakaran A, Pandey AK, Johnson JA, Zahid H, Hoell ZJ, Ellingson MO, Shi K, Aihara H, Harki DA. Selective N-terminal BRD4 bromodomain inhibitors by targeting non-conserved residues and structured water displacement. Angew Chem Int Ed Engl. 2020 Sep 24. doi: 10.1002/anie.202008625. PMID:32975004 doi:http://dx.doi.org/10.1002/anie.202008625

Contents


PDB ID 6wgx

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