2YEM: Crystal Structure Of The Second Bromodomain Of Human Brd4 With The Inhibitor Gw841819x

Citation:
Abstract
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.
PDB ID: 2YEMDownload
MMDB ID: 91739
PDB Deposition Date: 2011/3/25
Updated in MMDB: 2011/07
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 2YEM: dimeric; determined by author and by software (PISA)
Molecular Components in 2YEM
Label Count Molecule
Proteins (2 molecules)
2
Bromodomain-containing Protein 4(Gene symbol: BRD4)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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