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Structure. 2016 Jul 6;24(7):1201-8. doi: 10.1016/j.str.2016.04.019. Epub 2016 Jun 9.

Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4.

Author information

1
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
3
The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
4
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
6
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.

Abstract

The bromodomains and extra-terminal domain (BET) proteins direct gene transcription in chromatin, and represent new drug targets for cancer and inflammation. Here we report that the ET domain of the BET protein BRD4 recognizes an amphipathic protein sequence motif through establishing a two-strand antiparallel β sheet anchored on a hydrophobic cleft of the three-helix bundle. This structural mechanism likely explains BRD4 interactions with numerous cellular and viral proteins such as Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen, and NSD3 whose interaction with BRD4 via this ET domain mechanism is essential for acute myeloid leukemia maintenance.

PMID:
27291650
PMCID:
PMC4938737
DOI:
10.1016/j.str.2016.04.019
[Indexed for MEDLINE]
Free PMC Article

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