6v8k | pdb_00006v8k
Crystal structure of the p300 acetyltransferase domain with peptide-competitive inhibitor 2
Structural highlights
Disease[EP300_HUMAN] Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:613684]. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.[1] Function[EP300_HUMAN] Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acetylates FOXO1 and enhances its transcriptional activity.[2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedEP300 and CBP are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription via acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high-throughput screen of 191,000 compounds searching for EP300/CBP HAT inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including x-ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, AcCoA-competitive inhibitors, peptide-competitive inhibitors, and mixed/ allosteric inhibitors. The latter two classes of inhibitors have not been described before and the profiles of an exemplar of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA-competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of histone acetyltransferase inhibitors. Early Drug Discovery Efforts Towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors.,Wilson JE, Huhn A, Gardberg AS, Poy F, Brucelle F, Vivat V, Patel G, Patel C, Cummings R, Sims R, Levell J, Audia JE, Bommi-Reddy A, Cantone N ChemMedChem. 2020 Mar 17. doi: 10.1002/cmdc.202000007. PMID:32181984[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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