Institution
Structural Genomics Consortium
Nonprofit•Toronto, Ontario, Canada•
About: Structural Genomics Consortium is a nonprofit organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Protein structure & Kinase. The organization has 1047 authors who have published 1804 publications receiving 97694 citations.
Topics: Protein structure, Kinase, Histone, Bromodomain, Chromatin
Papers published on a yearly basis
Papers
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TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
3,489 citations
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TL;DR: Differential scanning fluorimetry (DSF) is a rapid and inexpensive screening method to identify low-molecular-weight ligands that bind and stabilize purified proteins.
Abstract: Differential scanning fluorimetry (DSF) is a rapid and inexpensive screening method to identify low-molecular-weight ligands that bind and stabilize purified proteins. The temperature at which a protein unfolds is measured by an increase in the fluorescence of a dye with affinity for hydrophobic parts of the protein, which are exposed as the protein unfolds. A simple fitting procedure allows quick calculation of the transition midpoint; the difference in the temperature of this midpoint in the presence and absence of ligand is related to the binding affinity of the small molecule, which can be a low-molecular-weight compound, a peptide or a nucleic acid. DSF is best performed using a conventional real-time PCR instrument. Ligand solutions from a storage plate are added to a solution of protein and dye, distributed into the wells of the PCR plate and fluorescence intensity measured as the temperature is raised gradually. Results can be obtained in a single day.
2,194 citations
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TL;DR: Bromodomains are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks, and a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4 is uncovered.
1,346 citations
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TL;DR: The key protein families that mediate epigenetic signalling through the acetylation and methylation of histones are reviewed, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones.
Abstract: Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.
1,184 citations
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TL;DR: Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted.
Abstract: Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.
1,090 citations
Authors
Showing all 1053 results
Name | H-index | Papers | Citations |
---|---|---|---|
Mark Gerstein | 168 | 751 | 149578 |
Timothy P. Hughes | 145 | 831 | 91357 |
Paul Brennan | 132 | 1221 | 72748 |
Janet M. Thornton | 130 | 539 | 105144 |
Peter Brown | 129 | 908 | 68853 |
David I. Stuart | 113 | 594 | 49733 |
Masayori Inouye | 111 | 652 | 43410 |
Barry Honig | 111 | 375 | 55150 |
Wei Zhang | 104 | 2911 | 64923 |
Nevan J. Krogan | 104 | 396 | 47254 |
Jack Greenblatt | 97 | 246 | 38129 |
Stefan Knapp | 95 | 536 | 32089 |
Cheryl H. Arrowsmith | 94 | 591 | 30660 |
Burkhard Rost | 93 | 322 | 38606 |
Christopher J. Schofield | 91 | 779 | 43471 |