3tlp
From Proteopedia
Crystal structure of the fourth bromodomain of human poly-bromodomain containing protein 1 (PB1)
Structural highlights
Disease[PB1_HUMAN] Defects in PBRM1 are a cause of renal cell carcinoma (RCC) [MIM:144700]. It is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.[1] Function[PB1_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Acts as a negative regulator of cell proliferation.[2] Publication Abstract from PubMedBromodomains (BRDs) are protein interaction modules that specifically recognize epsilon-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family. Histone recognition and large-scale structural analysis of the human bromodomain family.,Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S Cell. 2012 Mar 30;149(1):214-31. PMID:22464331[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Allerston, C K | Arrowsmith, C H | Bountra, C | Delft, F von | Edwards, A M | Felletar, I | Filippakopoulos, P | Keates, T | Knapp, S | Krojer, T | Latwiel, S | Muniz, J | Picaud, S | Structural genomic | Weigelt, J | Baf180 | Brg1-associated factor 180 | Bromodomain | Pb1 | Pbrm1 | Polybromo 1 isoform 1 | Polybromo-1d | Sgc | Transcription
