6ZS3

Crystal structure of the fifth bromodomain of human protein polybromo-1 in complex with 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol

Summary for 6ZS3

• Entry DOI: 10.2210/pdb6zs3/pdb
• Descriptor: Protein polybromo-1, 2-(6-azanyl-5-piperazin-4-ium-1-yl-pyridazin-3-yl)phenol, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, complex, small molecule, structural genomics consortium, sgc, transcription, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 29964.79

Authors

Preuss, F.,Joerger, A.C.,Wanior, M.,Kraemer, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-07-15, release date: 2020-10-07, Last modification date: 2024-01-31)

Primary citation

Wanior, M.,Preuss, F.,Ni, X.,Kramer, A.,Mathea, S.,Gobel, T.,Heidenreich, D.,Simonyi, S.,Kahnt, A.S.,Joerger, A.C.,Knapp, S.
Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis.
J.Med.Chem., 63:14680-14699, 2020

PubMed Abstract: Accessibility of the human genome is modulated by the ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated BAF factor), which involves reading of acetylated histone tails by the bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation of chromatin remodeling leads to aberrant cell proliferation and differentiation. Here, we have characterized a set of potent and cell-active bromodomain inhibitors with pan-selectivity for canonical family VIII bromodomains. Targeted SWI/SNF bromodomain inhibition blocked the expression of key genes during adipogenesis, including the transcription factors PPARγ and C/EBPα, and impaired the differentiation of 3T3-L1 murine fibroblasts into adipocytes. Our data highlight the role of SWI/SNF bromodomains in adipogenesis and provide a framework for the development of SWI/SNF bromodomain inhibitors for indirect targeting of key transcription factors regulating cell differentiation.

PubMed: 33216538
DOI: 10.1021/acs.jmedchem.0c01242

Experimental method

X-RAY DIFFRACTION (1.67 Å)