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From Proteopedia
Crystal structure of human EP300 KIX domain (L644C mutant)
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 PubMedSmall-cell lung cancer (SCLC) is highly lethal because the tumors grow and metastasize rapidly. Effective treatments for SCLC are lacking currently. A recent study demonstrated that the E1A binding protein P300 (EP300) KIX domain has pro-tumorigenic activity and is selectively involved in the development and growth of SCLC. These findings suggest the possibility of developing small-molecule inhibitors of EP300 KIX as new targeted therapies for SCLC. In this study, we reported the crystal structure of the human EP300 KIX domain at 2.9 A resolution except for a flexible loop and C-terminal end. The overall structure was almost identical to that of the cAMP response element-binding protein (CBP) KIX. Nine EP300 KIX residues were different from those of CBP KIX. Among these non-strictly conserved residues, Ala627, which corresponds to Asp647 in CBP KIX, reduces the negative surface potential. Asn581 and Arg613 contributed to the formation of additional hydrogen bonds in the EP300 KIX structure. Further structural analysis revealed that the hydrophobic residues that form the allosteric network in CBP KIX were well conserved in the EP300 KIX structure. This study lays the groundwork for structure-based drug design for SCLC. Comparative crystal structure analysis of the human EP300 and CBP KIX domains.,Cho SE, Lee Y, Kim JI, Jung KY, Jeong H, Park HW, Lee BI Biochem Biophys Res Commun. 2024 Dec 31;741:151064. doi: , 10.1016/j.bbrc.2024.151064. Epub 2024 Nov 26. PMID:39612645[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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