Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Tabackman, Alexa A.; Frankson, Rochelle; Marsan, Eric S.; Perry, Kay; Cole, Kathryn

doi:10.1016/j.jsb.2016.06.023

Cited by 58 publications

(39 citation statements)

References 30 publications

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“…In our model, the MTA H helix lies directly adjacent to the HDAC active site. Figure 2c highlights the well-described phenylalanine at the entry to the active site (Phe150, blue) and we have indicated the degree of access to the active site by modelling in a known HDAC inhibitor, hydroxamic acid (based on a structure of HDAC8; PDB: 5FCW) (49). This observation suggests that the MTA subunits in NuRD could potentially modulate HDAC activity.…”

Section: Xlms Data Establish the Core Architecture Of The Nurd Complexmentioning

confidence: 76%

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

Low

Silva

Tabar

et al. 2020

Preprint

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The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a 'moonlighting' PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity. INO80(1, 2) and SWR1 complexes (3), as well as to the Snf2 (4) and Chromodomain-Helicase-DNA-binding 1 (CHD1) remodelers (5), our understanding of how such enzymes bring about remodeling is still underdeveloped. This is particularly true for the nucleosome remodeling and deacetylase (NuRD) complex.The NuRD complex is widely distributed among Metazoans and is expressed in most, if not all, tissues. It is essential for normal development (6, 7) and is a key regulator in the reprogramming of differentiated cells into pluripotent stem cells (8-10). Age-related reductions in NuRD subunit levels are strongly associated with memory loss, metastatic potential in human cancers (11), and the accumulation of chromatin defects (12, 13).The mammalian NuRD complex comprises at least six subunits (Figure S1a), and for each subunit there are at least two paralogues, giving the potential for significant compositional heterogeneity. CHD4 (and its paralogues CHD3 and -5) is the ATP-dependent DNA translocase in the complex and harbours several regulatory and targeting domains. For example, the PHD domains of CHD4 can recognize histone H3 N-terminal tails bearing methyllysine marks (14-16), and the HMG domain has been shown to bind to poly-ADP(ribose) (17). What distinguishes NuRD from many other remodelers is that it harbours a second catalytic activity, imparted by the histone deacetylases HDAC1 and -2. MBD2 and -3 can bind hydroxymethylated and/or methylated , and RBBP4 and -7 can each bind histone tails (21) and other transcriptional regulators (22,23). The metastasis-associated proteins MTA1, -2 and -3 contain several domains that are associated with nucleosome recognition, whereas GATAD2A and GATAD2B bind to both 25) and CHD proteins (25, 26) but otherwise do not have known functions. Some structural information is available for portions of t...

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Section: Xlms Data Establish the Core Architecture Of The Nurd Complexmentioning

confidence: 76%

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

Low

Silva

Tabar

et al. 2020

Preprint

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“…The compounds were modelled and minimized using MacroModel (2018-4, Schrödinger, LLC, New York, NY, 2018) and OPLS 2005 force field parameters [23]. The crystal structure of HDAC 1 (PDB ID: 5ICN), HDAC 2 (PDB ID: 4LXZ), HDAC 3 (PDB ID: 4A69) and HDAC 8 (PDB ID: 5FCW) was downloaded from RCSB Protein Data Bank (www.rcsb.org) and prepared for docking with the Protein Preparation Wizard (2018-4, Schrödinger, LLC, NY, 2018) of Maestro (2018-4, Schrödinger, LLC, NY, 2018) [23,[33][34][35][36][37]. In this procedure unwanted residues were removed and the protons were handled with Epik (2018-4, Schrödinger, LLC, New York, NY, 2018), water orientations were sampled and H bonds were set with Propka.…”

Section: Molecular Modelingmentioning

confidence: 99%

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

Bora¹,

Sarı²,

Taşkor³

et al. 2019

jrp

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Histone deacetylases (HDAC) are evolutionary conserved enzymes, which catalyze removal of acetyl groups from histone and non-histone proteins, therefore, control multiple biological processes. Inhibition of their activities have been investigated to modify gene expression and/or protein functions not only for treatment of certain diseases but also for understanding functions of deacetylase isoforms. We previously synthesized aryl butenoic acid derivatives and identified their pan-HDAC inhibition activities. In this study, we investigated selective inhibition activities of these derivatives (C1, C3, C4) on class I HDACs using in silico and in vitro approaches. Molecular docking studies of the three aryl butenoic acid derivatives were performed on the crystal structures of HDAC 1, 2, 3 and 8, which were obtained from RCSB protein databank, using Glide software. In vitro inhibition activities of the compounds at two different concentrations were tested using fluorometric assay. In silico results indicated that all the compounds showed higher affinity to HDAC 1 and 8 than other class I deacetylases. In vitro analysis showed that the compounds inhibit HDAC 8 more effectively than HDAC 1. It was shown that C1 had higher binding affinity and inhibition activity to both enzymes. We concluded that, C1 inhibited both HDAC 1 and 8, however, C3 and C4 showed slight selectivity for HDAC 8 over HDAC 1, which was in agreement with the docking studies. Further cell culture studies will be valuable to determine increased acetylation on target proteins in response to compound treatment.

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“…To our knowledge, this is the first report which states that Type I ribosomal inactivating proteins derived from dietary bitter melon possess HDACi activity and can selectively induce apoptosis in premalignant and malignant prostate cells and inhibit human prostate cancer cell growth in vivo. [136,137] Inflammation and bitter melon Inflammation is a complicated immune process that can be defined by the sequential release of mediators such as pro-inflammatory cytokines, including interleukin (IL)-1, tumour necrosis factor (TNF), interferon (IFN)-c, IL-6, IL-12, IL-18, and the granulocyte-macrophage colony stimulating factor. Inflammation is settled by anti-inflammatory cytokines such as IL-4, IL-10, IL-13, IFN-a, and the transforming growth factor (TGF)-b.…”

Section: Antioxidant and Antiinflammatory Activitymentioning

confidence: 99%

Bitter melon (Momordica charantia): a natural healthy vegetable

Saeed

Afzaal

Niaz

et al. 2018

International Journal of Food Properties

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Bitter melon provides health benefits against various ailments for improving the quality of life. It is nutrient dense plant-based food containing versatility of bioactive compounds such as alkaloids, polypeptide, vitamins, and minerals. Owing to presence of bioactive compounds, it has the ability to fight against various lifestyle related disorders, e.g. cancer insurgence, diabetes mellitus, abdominal pain, kidney (stone), fever, and scabies. Amongst bioactive moieties, p-insulin is similar to insulin whose subcutaneous injection significantly lower blood glucose levels in diabetic patients. It also contains steroidal saponins called charantin, act alike peptides and certain alkaloids that effectively control sugar level in blood. The therapeutic perspectives have been also highlighted as they are helpful in regulating blood cholesterol thus protecting the body from cardiovascular disorders like atherosclerosis. Whole fruit, seeds and leaves of bitter melon regulates impaired antioxidant status and suppress fat accumulation. Moreover, curative potential of its bioactive components and their utilization in value added food products are also the limelight of article.

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Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Cited by 58 publications

References 30 publications

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

Bitter melon (Momordica charantia): a natural healthy vegetable

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