PDBsum entry 6djc

Transcription/inhibitor

PDB id: 6djc

Contents

Protein chains

131 a.a.

Ligands

CF6

EDO ×8

Waters ×350

PDB id:

6djc

Name:

Transcription/inhibitor

Title:

Crystal structure of human bromodomain-containing protein 4 (brd4) bromodomain with ms645

Structure:

Bromodomain-containing protein 4. Chain: a, b. Synonym: protein hunk1. Engineered: yes. Other_details: proteolysis during crystallization

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.46Å R-factor: 0.143 R-free: 0.176

Authors:

C.Ren,M.M.Zhou

Key ref:

C.Ren et al. (2018). Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth. Proc Natl Acad Sci U S A, 115, 7949-7954. PubMed id: 30012592 DOI: 10.1073/pnas.1720000115

Date:

25-May-18 Release date: 25-Jul-18

Protein chains

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 131 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1073/pnas.1720000115

Proc Natl Acad Sci U S A 115:7949-7954 (2018)

PubMed id: 30012592

Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

C.Ren, G.Zhang, F.Han, S.Fu, Y.Cao, F.Zhang, Q.Zhang, J.Meslamani, Y.Xu, D.Ji, L.Cao, Q.Zhou, K.L.Cheung, R.Sharma, N.Babault, Z.Yi, W.Zhang, M.J.Walsh, L.Zeng, M.M.Zhou.

ABSTRACT

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.