8fv2

Bromodomain of CBP liganded with CCS-1477

spinqualitylabelsall models 8fv2, resolution 1.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fv2 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.87Å Ligands: EDO, JHL, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CBP_HUMAN Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:180849. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Function CBP_HUMAN Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300. Publication Abstract from PubMed Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB. Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.,Shendy NAM, Bikowitz M, Sigua LH, Zhang Y, Mercier A, Khashana Y, Nance S, Liu Q, Delahunty IM, Robinson S, Goel V, Rees MG, Ronan MA, Wang T, Kocak M, Roth JA, Wang Y, Freeman BB, Orr BA, Abraham BJ, Roussel MF, Schonbrunn E, Qi J, Durbin AD Nat Commun. 2024 Apr 25;15(1):3483. doi: 10.1038/s41467-024-47102-0. PMID:38664416 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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