Summary
PDB 4A9L deposited: 2011-11-26 modified: 2012-02-08
Title N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 1,3-DIMETHYL-6-(MORPHOLINE- 4-SULFONYL)-1,2,3,4-TETRAHYDROQUINAZOLIN-2-ONE
Authors Bamborough, P., Chung, C.W., Dean, A.W., Woolven, J.M.
Method X-RAY DIFFRACTION
Structure factors resolution 1.6 rfactor 0.17801 rfree 0.206
DPI 0.27 theoretical min: 0.09
Related PDB Entries 4A9E 4A9F 4A9H 4A9I 4A9J 4A9K
Citations

Bromodomain-containing proteins are key epigenetic regulators of gene transcription and readers of the histone code. However, the therapeutic benefits of modulating this target class are largely unexplored due to the lack of suitable chemical probes. This article describes the generation of lead molecules for the BET bromodomains through screening a fragment set chosen using structural insights and computational approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights both shared and disparate interaction features that may be exploited for affinity and selectivity. Six representative crystal structures are then exemplified in detail. Two of the fragments are completely new bromodomain chemotypes, and three have never before been crystallized in a bromodomain, so our results significantly extend the limited public knowledge-base of crystallographic small molecule/bromodomain interactions. Certain fragments (including paracetamol) bind in a consistent mode to different bromodomains such as CREBBP, suggesting their potential to act as generic bromodomain templates. An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others.

J.Med.Chem. 2012 Jan; 55(2):576- doi:10.1021/JM201320W

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1949574
PubMed 22136404 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4A9L/0 4A9L 0 monomer 0 1 6 1244