5gtc
Crystal structure of complex between DMAP-SH conjugated with a Kaposi's sarcoma herpesvirus LANA peptide (5-15) and nucleosome core particle
Structural highlights
FunctionH2B1J_HUMAN Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.[1] [2] [3] Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.[4] [5] [6] Publication Abstract from PubMedPosttranslational modifications (PTMs) of histones play an important role in the complex regulatory mechanisms governing gene transcription, and their dysregulation can cause diseases such as cancer. The lack of methods for site-selectively modifying native chromatin, however, limits our understanding of the functional roles of a specific histone PTM, not as a single mark, but in the intertwined PTM network. Here, we report a synthetic catalyst DMAP-SH (DSH), which activates chemically stable thioesters (including acetyl-CoA) under physiological conditions and transfers various acyl groups to the proximate amino groups. Our data suggest that DSH, conjugated with a nucleosome ligand, such as pyrrole-imidazole-polyamide and LANA (latency-associated nuclear antigen)-peptide, promotes both natural (including acetylation, butyrylation, malonylation, and ubiquitination) and non-natural (azido- and phosphoryl labeling) PTMs on histones in recombinant nucleosomes and/or in native chromatin, at lysine residues close to the DSH moiety. To investigate the validity of our method, we used LANA-DSH to promote histone H2B lysine-120 (K120) acylation, the function of which is largely unknown. H2BK120 acetylation and malonylation modulated higher-order chromatin structures by reducing internucleosomal interactions, and this modulation was further enhanced by histone tail acetylation. This approach, therefore, may have versatile applications for dissecting the regulatory mechanisms underlying chromatin function. Synthetic Posttranslational Modifications: Chemical Catalyst-Driven Regioselective Histone Acylation of Native Chromatin.,Amamoto Y, Aoi Y, Nagashima N, Suto H, Yoshidome D, Arimura Y, Osakabe A, Kato D, Kurumizaka H, Kawashima SA, Yamatsugu K, Kanai M J Am Chem Soc. 2017 Jun 7;139(22):7568-7576. doi: 10.1021/jacs.7b02138. Epub 2017, May 23. PMID:28534629[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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