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4A9K

BROMODOMAIN OF HUMAN CREBBP WITH N-(4-hydroxyphenyl)acetamide

Summary for 4A9K
Entry DOI10.2210/pdb4a9k/pdb
Related1JSP 1LIQ 1WO3 1WO4 1WO5 1WO6 1WO7 2D82
DescriptorCREB-BINDING PROTEIN, 1,2-ETHANEDIOL, N-(4-HYDROXYPHENYL)ACETAMIDE (TYLENOL), ... (6 entities in total)
Functional Keywordsinhibitor, histone, epigenetic reader, signaling protein
Biological sourceHOMO SAPIENS (HUMAN)
Total number of polymer chains2
Total formula weight28970.34
Authors
Chung, C.W.,Bamborough, P. (deposition date: 2011-11-26, release date: 2012-01-11, Last modification date: 2024-05-08)
Primary citationChung, 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: 22136404
DOI: 10.1021/JM201320W
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.81 Å)
Structure validation

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