5lpm | pdb_00005lpm
Crystal structure of the bromodomain of human Ep300 bound to the inhibitor XDM3d
Structural highlights
DiseaseEP300_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] FunctionEP300_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 PubMedBET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. In addition to X-ray crystal structure analysis and thermodynamic profiling, we used XDM-CBP in in vitro cell screenings of several cancer cell lines to study its inhibitory potential on cancer cell proliferation. Our results demonstrate that XDM-CBP is a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia. Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles.,Hugle M, Lucas X, Ostrovskyi D, Regenass P, Gerhardt S, Einsle O, Hau M, Jung M, Breit B, Gunther S, Wohlwend D Angew Chem Int Ed Engl. 2017 Aug 2. doi: 10.1002/anie.201705516. PMID:28766825[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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