Competitive Binding of a Benzimidazole to the Histone-Binding Pocket of the Pygo PHD Finger

ABSTRACT The ING (inhibitor of growth) protein family includes a group of homologous nuclear proteins that share a highly conserved plant homeodomain (PHD) finger domain at their carboxyl termini. Members of this family are found in multiprotein complexes that posttranslationally modify histones, suggesting that these proteins serve a general role in permitting various enzymatic activities to interact with nucleosomes. There are three members of the ING family in Saccharomyces cerevisiae: Yng1p, Yng2p, and Pho23p. Yng1p is a component of the NuA3 histone acetyltransferase complex and is required for the interaction of NuA3 with chromatin. To gain insight into the function of the ING proteins, we made use of a genetic strategy to identify genes required for the binding of Yng1p to histones. Using the toxicity of YNG1 overexpression as a tool, we showed that Yng1p interacts with the amino-terminal tail of histone H3 and that this interaction can be disrupted by loss of lysine 4 methylation within this tail. Additionally, we mapped the region of Yng1p required for overexpression of toxicity to the PHD finger, showed that this region capable of binding lysine 4-methylated histone H3 in vitro, and demonstrated that mutations of the PHD finger that abolish binding in vitro are no longer toxic in vivo. These results identify a novel function for the Yng1p PHD finger in promoting stabilization of the NuA3 complex at chromatin through recognition of histone H3 lysine 4 methylation.

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Inhibition of histone binding by supramolecular hosts

Biochemical Journal ◽

10.1042/bj20140145 ◽

2014 ◽

Vol 459 (3) ◽

pp. 505-512 ◽

Cited By ~ 34

Author(s):

Hillary F. Allen ◽

Kevin D. Daze ◽

Takashi Shimbo ◽

Anne Lai ◽

Catherine A. Musselman ◽

...

Keyword(s):

Histone Tail ◽

Histone Binding ◽

Phd Finger

We report a new set of calixarene-based host compounds and show their applicability in characterizing functions of methyllysine-recognizing epigenetic readers. Calixarenes disrupt the association of the PHD finger of CHD4 with a trimethylated, but not an unmodified, histone tail.

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Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b

Nature ◽

10.1038/nature09139 ◽

2010 ◽

Vol 466 (7303) ◽

pp. 258-262 ◽

Cited By ~ 186

Author(s):

Lei Zeng ◽

Qiang Zhang ◽

SiDe Li ◽

Alexander N. Plotnikov ◽

Martin J. Walsh ◽

...

Keyword(s):

Histone Binding ◽

Phd Finger

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The BRPF1 bromodomain is a molecular reader of di-acetyllysine

10.1101/2020.02.13.948091 ◽

2020 ◽

Author(s):

Juliet O. Obi ◽

Mulu Y. Lubula ◽

Gabriel Cornilescu ◽

Amy Henrickson ◽

Kara McGuire ◽

...

Keyword(s):

Zinc Finger Protein ◽

Analytical Ultracentrifugation ◽

Binding Pocket ◽

Histone H4 ◽

Histone Tail ◽

Tail Region ◽

Pwwp Domain ◽

Altered Expression ◽

Phd Finger ◽

Finger Protein

ABSTRACTBromodomain-containing proteins are often part of chromatin-modifying complexes, and their activity can lead to altered expression of genes that drive cancer, inflammation and neurological disorders in humans. Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ (monocytic leukemic zinc-finger protein) HAT (histone acetyltransferase) complex, which is associated with chromosomal translocations known to contribute to the development of acute myeloid leukemia (AML). BRPF1 contains a unique combination of chromatin reader domains including two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain. BRPF1 is known to recruit the MOZ HAT complex to chromatin by recognizing acetylated lysine residues on the N-terminal histone tail region through its bromodomain. However, histone proteins can contain several acetylation modifications on their N-terminus, and it is unknown how additional marks influence bromodomain recruitment to chromatin. Here, we identify the BRPF1 bromodomain as a selective reader of di-acetyllysine modifications on histone H4. We used ITC assays to characterize the binding of di-acetylated histone ligands to the BRPF1 bromodomain and found that the domain binds preferentially to histone peptides H4K5acK8ac and H4K5acK12ac. Analytical ultracentrifugation (AUC) experiments revealed that the monomeric state of the BRPF1 bromodomain coordinates di-acetylated histone ligands. NMR chemical shift perturbation studies, along with binding and mutational analyses, revealed non-canonical regions of the bromodomain-binding pocket that are important for histone tail recognition. Together, our findings provide critical information on how the combinatorial action of post-translational modifications can modulate BRPF1 bromodomain binding and specificity.

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Allosteric Remodelling of the Histone H3 Binding Pocket in the Pygo2 PHD Finger Triggered by Its Binding to the B9L/BCL9 Co-Factor

Journal of Molecular Biology ◽

10.1016/j.jmb.2010.07.007 ◽

2010 ◽

Vol 401 (5) ◽

pp. 969-984 ◽

Cited By ~ 32

Author(s):

Thomas C.R. Miller ◽

Trevor J. Rutherford ◽

Christopher M. Johnson ◽

Marc Fiedler ◽

Mariann Bienz

Keyword(s):

Histone H3 ◽

Binding Pocket ◽

Phd Finger

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Characterization of Recombinant Human Coagulation Factor XFriuli

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650267 ◽

1996 ◽

Vol 75 (02) ◽

pp. 313-317 ◽

Cited By ~ 8

Author(s):

D J Kim ◽

A Girolami ◽

H L James

Keyword(s):

Catalytic Domain ◽

Coagulation Factor ◽

Molecular Size ◽

Binding Pocket ◽

Site Directed Mutagenesis ◽

Bleeding Tendency ◽

Factor X ◽

Amino Terminal ◽

Normal Plasma ◽

Plasma Factor

SummaryNaturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational y-carboxy-glutamic acid (Gla) and (β-hydroxy aspartic acid (β-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel (3-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

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DESIGN OF NEW PEROXISOME PROLIFERATORS GAMMA ACTIVATED RECEPTOR AGONISTS (PPARγ) VIA QSAR BASED MODELING

Journal of Applied Pharmaceutical Sciences and Research ◽

10.31069/japsr.v1i01.13059 ◽

2018 ◽

pp. 23-26 ◽

Cited By ~ 1

Author(s):

Tripathi RB ◽

Jain J ◽

Siddiqui AW

Keyword(s):

Molecular Descriptor ◽

Binding Pocket ◽

Peroxisome Proliferators ◽

Qsar Study ◽

Qsar Analysis ◽

Qsar Models ◽

Artery Disease ◽

Peroxisome Proliferators Activated Receptors ◽

Recent Attention

The Peroxisome proliferators-activated receptors (PPARs) are one of the nuclear fatty acid receptors, which contain a type II zincfinger DNA binding pattern and a hydrophobic ligand binding pocket. These receptors are thought to play an essential role in metabolic diseasessuch as obesity, insulin resistance, and coronary artery disease. Therefore Peroxisome Proliferators-Activated Receptor (PPARγ) activators havedrawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize newPPARγ activators. Objective: The aim of the study was to finding new selective human PPARγ (PPARγ) modulators that are able to improveglucose homeostasis with reduced side effects compared with TZDs and identify the specific molecular descriptor and structural constraint toimprove the agonist activity of PPARγ analogs. Material and Method: Software’s that was used for this study include S.P. Gupta QSARsoftware (QSAR analysis), Valstat (Comparative QSAR analysis and calculation of L-O-O, Q2, r2, Spress), BILIN (Comparative QSAR analysisand calculation of Q2, r, S, Spress, and F), etc., allowing directly performing statistical analysis. Then multiple linear regression based QSARsoftware (received from BITS-Pilani, India) generates QSAR equations. Result and Discussion: In this study, we explored the quantitativestructure–activity relationship (QSAR) study of a series of meta-substituted Phenyl-propanoic acids as Peroxisome Proliferators Gamma activatedreceptor agonists (PPARγ).The activities of meta-substituted Phenyl-propanoic acids derivatives correlated with various physicochemical, electronic and steric parameters.Conclusion: The identified QSAR models highlighted the significance of molar refractivity and hydrophobicity to the biological activity.

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