Molecular Recognition of Lys and Arg Methylation

Beaver, Joshua E.; Waters, Marcey L.

doi:10.1021/acschembio.5b00996

Cited by 67 publications

(70 citation statements)

References 96 publications

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“…112 Perhaps the ultimate challenge in protein recognition -the recognition of individual residues on an open surface -is difficult, but pioneering work has shown that rare residues such as those post-translationally modified in histone proteins can be successfully targeted. 113 What about enzyme mimicry? The important difference between synthetic hosts and biological ones is one of size, and this leads to other important differences including: polarity, flexibility, and intricacy of the binding motif.…”

Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry. AbstractOn planet Earth, water is everywhere: the majority of the surface is covered with it; it is a key component of all life; its vapor and droplets fill the lower atmosphere; even rocks contain it and undergo geomorphological changes because of it. A community of physical scientists largely drives studies of the chemistry of water and aqueous solutions, with expertise in biochemistry, spectroscopy, and computer modeling. More recently however, supramolecular chemistry -with its expertise in macrocyclic synthesis and measuring supramolecular interactions -have renewed their interest in water-mediated non-covalent interactions. These two groups offer complementary expertise that, if harnessed, offers to accelerate our understanding of aqueous supramolecular chemistry and water writ large. This review summarizes the state-of-the-art of the two fields, and highlights where there is latent chemical space for collaborative exploration by the two groups. 4Water is ubiquitous and essential to life on planet Earth. A full understanding of aqueous solutions is therefore of significance to a wide range of fields within the atmospheric, environmental, biological and geological sciences. Within the chemical sciences, a deeper appreciation of how non-covalent interactions and chemical transformations are influenced by water would benefit a variety of fields. However, as we highlight here, there are many open questions regarding the chemical and physical properties of aqueous solutions.The aqueous realm is frequently bifurcated into the Hofmeister and hydrophobic effects, phenomena that respectively deal with the properties of solutions of salts and relatively nonpolar molecules. However, it is becoming increasingly evident that these areas do in fact frequently overlap; two prime examples being the accumulation of large polarizable anions at the air-water interface, 1-5 and the favorable interactions of polarizable anions with non-polar surfaces. [6][7][8][9][10][11][12][13][14][15] Thus the hydrophobic and Hofmeister effects are but part of a greater continuum of aqueous supramolecular chemistry, with many important and outstanding questions regarding the influence of the different kinds of non-covalent interactions involved.Studies of water and aqueous solutions have mostly been driven by the physical sciences community, a broad range of scientists whose expertise in spectroscopy, computer modeling, and biochemistry (to name just three areas) has generally not involved macrocycles or host molecules in general. However, for some time now, supramolecular chemists -with their expertise in macrocyclic synthesis and measuring weak non-covalent interactions -have been travelling a parallel course of exploration. This Review, inspired by discussions between sixteen members of each community at a recent workshop, 16 is an attempt to summarize what we know about aqueous solutions, what we do not know about them, and where the two communit...

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Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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“…As a consequence, epigenetic regulators have become major targets for drug development 9 . Lysine and arginine methylation play central roles in this “histone code” theory, and these two residues can accept more than one methyl group, with different protein methyltransferases able to execute varying degrees of methylation 10 . Methyl reader domains are clustered into eight major families, including plant homeodomains (PHDs), WD-40 domains, chromatin organization modifier domains (chromodomains), Tudor domains, Agenet domains, proline-tryptophan-tryptophan-proline (PWWP) domains, Bromo adjacent homology (BAH) domains, and malignant brain tumor (MBT) domains 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Developing Spindlin1 small-molecule inhibitors by using protein microarrays

Bae

Viviano

et al. 2017

Nat Chem Biol

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The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the “druggability” of epigenetic effector molecules. The small molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains, and with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs we screened a protein domain microarray of human methyl-lysine effector molecules to rapidly detect compounds with novel binding profiles - either improved or loosened specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of more selective SPIN1 inhibitors (EML631–633), which engage SPIN1 in cells, block its ability to “read” H3K4me3 marks, and inhibit its transcriptional coactivator activity. Protein microarrays can thus be used as a platform to “target hop” and identify small molecules that bind and compete with domain–motif interactions.

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“…Histone methylation is completed by S-adenosylmethionine-dependent methyltransferase and occurs on lysine or arginine residues in histone tails (Beaver and Waters, 2016). Histone methylation has been shown to play a role in both transcriptional activation and repression (Wang et al, 2001; Jeong et al, 2011; Kallestad et al, 2014; Figure 2B).…”

Section: Mechanismsmentioning

confidence: 99%

Epigenetics in Schistosomes: What We Know and What We Need Know

Liu

2016

Front. Cell. Infect. Microbiol.

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Schistosomes are metazoan parasites and can cause schistosomiasis. Epigenetic modifications include DNA methylation, histone modifications and non-coding RNAs. Some enzymes involved in epigenetic modification and microRNA processes have been developed as drugs to treat the disease. Compared with humans and vertebrates, an in-depth understanding of epigenetic modifications in schistosomes is starting to be realized. DNA methylation, histone modifications and non-coding RNAs play important roles in the development and reproduction of schistosomes and in interactions between the host and schistosomes. Therefore, exploring and investigating the epigenetic modifications in schistosomes will facilitate drug development and therapy for schistosomiasis. Here, we review the role of epigenetic modifications in the development, growth and reproduction of schistosomes, and the interactions between the host and schistosome. We further discuss potential epigenetic targets for drug discovery for the treatment of schistosomiasis.

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Molecular Recognition of Lys and Arg Methylation

Cited by 67 publications

References 96 publications

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Developing Spindlin1 small-molecule inhibitors by using protein microarrays

Epigenetics in Schistosomes: What We Know and What We Need Know

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