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      A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex

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          Abstract

          Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET ( bromodomain and extra- terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.

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          Most cited references 23

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          The structure of DNA in the nucleosome core.

          The 1.9-A-resolution crystal structure of the nucleosome core particle containing 147 DNA base pairs reveals the conformation of nucleosomal DNA with unprecedented accuracy. The DNA structure is remarkably different from that in oligonucleotides and non-histone protein-DNA complexes. The DNA base-pair-step geometry has, overall, twice the curvature necessary to accommodate the DNA superhelical path in the nucleosome. DNA segments bent into the minor groove are either kinked or alternately shifted. The unusual DNA conformational parameters induced by the binding of histone protein have implications for sequence-dependent protein recognition and nucleosome positioning and mobility. Comparison of the 147-base-pair structure with two 146-base-pair structures reveals alterations in DNA twist that are evidently common in bulk chromatin, and which are of probable importance for chromatin fibre formation and chromatin remodelling.
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            How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers.

            Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), especially on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their associated complexes, is predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here we summarize key features in molecular recognition of histone PTMs by a diverse family of 'reader pockets', highlighting specific readout mechanisms for individual marks, common themes and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biology and disease, notably cancer.
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              RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.

              Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                31 May 2016
                2016
                : 11
                : 5
                Affiliations
                Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
                NCI-Frederick, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BP ST. Performed the experiments: ST SM PD RM BP. Analyzed the data: BP ST SM PD. Contributed reagents/materials/analysis tools: BP. Wrote the paper: BP ST SM.

                Article
                PONE-D-16-09332
                10.1371/journal.pone.0156344
                4886958
                27243809
                © 2016 Tripathi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 8, Tables: 1, Pages: 17
                Product
                Funding
                BP is grateful to the Department of Biotechnology (DBT) (No. BT/PR7079/BID/7/426/2012), and Department of Science and Technology (DST) (No. SR/SO/BB-0108/2012) Government of India, India for the financial support; SM to DST for DST WOS-A fellowship (SR/WOS-A/LS-100/2013); RM is thankful to Council of Scientific and Industrial Research (CSIR) for SRF fellowship (09/490(0093)2012-EMR-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Physics
                Condensed Matter Physics
                Solid State Physics
                Crystallography
                Crystal Structure
                Physical Sciences
                Chemistry
                Physical Chemistry
                Chemical Bonding
                Hydrogen Bonding
                Physical Sciences
                Chemistry
                Chemical Physics
                Molecular Structure
                Physical Sciences
                Physics
                Chemical Physics
                Molecular Structure
                Physical Sciences
                Physics
                Condensed Matter Physics
                Electron Density
                Research and Analysis Methods
                Chemical Characterization
                Binding Analysis
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Histones
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromatin
                Biology and Life Sciences
                Genetics
                Epigenetics
                Chromatin
                Biology and Life Sciences
                Genetics
                Gene Expression
                Chromatin
                Research and Analysis Methods
                Crystallographic Techniques
                X-Ray Crystallography
                Research and Analysis Methods
                Structural Characterization
                X-Ray Crystallography
                Custom metadata
                The coordinate files are available from the wwPDB database (accession number(s) 5IBN, 5IG6).

                Uncategorized

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