7wwz

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BRD4-BD1 complexed with NEO2734

Structural highlights

7wwz 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 1.16Å
Ligands:7OW
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

CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.

Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.,Ji D, Shang G, Wei E, Jia Y, Wang C, Zhang Q, Zeng L Oncogene. 2022 Jun;41(23):3251-3262. doi: 10.1038/s41388-022-02327-5. Epub 2022, May 5. PMID:35513563[3]

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

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Citations
1 reviews cite this structure
Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.
Talukdar et al. (2023)
0 more
4 other articles
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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. ↑ Ji D, Shang G, Wei E, Jia Y, Wang C, Zhang Q, Zeng L. Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer. Oncogene. 2022 Jun;41(23):3251-3262. doi: 10.1038/s41388-022-02327-5. Epub 2022, May 5. PMID:35513563 doi:http://dx.doi.org/10.1038/s41388-022-02327-5

Contents


PDB ID 7wwz

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OCA

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