Structural Biology of Epigenetic Targets

Abstract

The dynamic remodeling of chromatin is essential to most DNA-based nuclear processes [1,2], and it comes as no surprise that epigenetic changes are implicated not only in normal development but also in various diseases, including cancer [3][4][5]. The intricacy of epigenetic mechanisms is shown by the large number of possible epigenetic marks [6] and the discovery that these marks not only destabilize nucleosomes but help in recruiting other epigenetic effectors to specific locations -information which led to the histone code hypothesis [7,8]. Consequently, the number of studies in the past two decades dedicated to deciphering these mechanisms and their effectors at the cellular and molecular levels followed an almost exponential growth [9].This large effort was accompanied by a wealth of structural data on epigenetic effectors in an attempt to understand epigenetic mechanisms at the atomic level. Certainly, the most impressive achievement was the crystallographic structure of the nucleosome [10] that showed not only how the DNA is wrapped around the (H2A/H2B)-(H3/H4) 2 -(H2A/H2B) histone octamer, but also how histone tails, the main targets of histone-modifying enzymes, interact with DNA. This structure represented a cornerstone in the field of epigenetics as, for the following biochemical and structural studies, it provided a first view on how DNA recognition sites and epigenetic marks might be presented to incoming effectors.Structural studies also embraced all epigenetic effectors in an effort to understand their structure/function relationships. Thanks to the large progress of structural biology in fields as diverse as biochemistry, molecular biology, nuclear magnetic resonance, X-ray crystallography and computer hardware and software, three-dimensional structures of epigenetic effectors have been obtained, either in a free state or in complex with cofactors and/or peptide substrates from target proteins. So far, most of the structural work has been carried out on individual, defined modules bearing either a catalytic activity, as described in this chapter, or responsible for the specific Epigenetic Targets in Drug Discovery. Edited by Wolfgang Sippl and Manfred Jung

Advances in Label-Free Screening Approaches for Studying Histone Acetyltransferases

“…5 Despite the lack of sequence similarity between the three best-characterized families, GNAT, MYST, and p300/CBP, protein members share a similar structural core, affinity for acetylating histone tails, and binding pocket for the acetyl donor molecule, acetyl-coenzyme A (AcCoA). 6,7…”