5h1v
Complex structure of TRIM24 PHD-bromodomain and inhibitor 6
Structural highlights
DiseaseTIF1A_HUMAN Defects in TRIM24 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=A chromosomal aberration involving TRIM24/TIF1 is found in thyroid papillary carcinomas. Translocation t(7;10)(q32;q11) with RET. The translocation generates the TRIM24/RET (PTC6) oncogene. FunctionTIF1A_HUMAN Transcriptional coactivator that interacts with numerous nuclear receptors and coactivators and modulates the transcription of target genes. Interacts with chromatin depending on histone H3 modifications, having the highest affinity for histone H3 that is both unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-23' (H3K23ac). Has E3 protein-ubiquitin ligase activity. Promotes ubiquitination and proteasomal degradation of p53/TP53. Plays a role in the regulation of cell proliferation and apoptosis, at least in part via its effects on p53/TP53 levels. Up-regulates ligand-dependent transcription activation by AR, GCR/NR3C1, thyroid hormone receptor (TR) and ESR1. Modulates transcription activation by retinoic acid (RA) receptors, including RARA. Plays a role in regulating retinoic acid-dependent proliferation of hepatocytes (By similarity).[1] [2] [3] Publication Abstract from PubMedTripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors. Interestingly, the polar substitution on the warhead of one new inhibitor pulls the whole ligand approximately 2 A into the inner side pocket of the TRIM24 bromodomain, and thus exhibits a binding mode significantly different from other known bromodomain ligands. This mode provides a useful handle for further hit-to-lead evolution towards novel inhibitors of the TRIM24 bromodomain. This article is protected by copyright. All rights reserved. The Polar Warhead of a TRIM24 Bromodomain Inhibitor Rearranges a Water-Mediated Interaction Network.,Liu J, Li F, Bao H, Jiang Y, Zhang S, Ma R, Gao J, Wu J, Ruan K FEBS J. 2017 Feb 16. doi: 10.1111/febs.14041. PMID:28207202[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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