4A9L
N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 1,3-DIMETHYL-6-(MORPHOLINE- 4-SULFONYL)-1,2,3,4-TETRAHYDROQUINAZOLIN-2-ONE
Summary for 4A9L
| Entry DOI | 10.2210/pdb4a9l/pdb |
| Related | 2YEL 2YEM 3ZYU 4A9E 4A9F 4A9H 4A9I 4A9J 4A9K |
| Descriptor | BROMODOMAIN-CONTAINING PROTEIN 4, 1,2-ETHANEDIOL, 1,3-dimethyl-6-(morpholin-4-ylsulfonyl)-3,4-dihydroquinazolin-2(1H)-one, ... (5 entities in total) |
| Functional Keywords | inhibitor, histone, epigenetic reader, signaling protein |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Nucleus (By similarity): O60885 |
| Total number of polymer chains | 1 |
| Total formula weight | 15734.98 |
| Authors | Chung, C.W.,Bamborough, P. (deposition date: 2011-11-26, release date: 2012-01-11, Last modification date: 2024-05-08) |
| Primary citation | Chung, C.W.,Dean, A.W.,Woolven, J.M.,Bamborough, P. Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery. J.Med.Chem., 55:576-, 2012 Cited by PubMed Abstract: 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. PubMed: 22136404DOI: 10.1021/JM201320W PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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