A Simple Calixarene Recognizes Post‐translationally Methylated Lysine

Beshara, Cory S.; Jones, C. E.; Daze, Kevin D.; Lilgert, Brandin J.; Hof, Fraser

doi:10.1002/cbic.200900633

Cited by 93 publications

(94 citation statements)

References 34 publications

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“…Due to the limited solubility of 1, it was not possible to obtain binding constants for compounds 10 and 11, which showed no or very little chemical shift changes (≤0.01 ppm) upon addition of 1 in the initial NMR experiments. Interestingly, in contrast to other reported methyllysine-binding macrocycles like tetrasulfonatocalixarene, 24 carboxycalixarene 1 has a similar affinity to Kme3 and Kme2 and is selective over Kme1 and Kme0, which is different to the selectivity profile of the reported tetrasulfonatocalixarene.…”

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confidence: 48%

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Selective recognition of the di/trimethylammonium motif by an artificial carboxycalixarene receptor

et al. 2017

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Chemical tools that recognise post-translational modifications have promising applications in biochemistry and in therapy. We report a simple carboxycalixarene that selectively binds molecules containing di/trimethylammonium moieties in isolation, in cell lysates and when incorporated in histone peptides. Our findings reveal the potential of using carboxycalixarene-based receptors to study epigenetic regulation.

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confidence: 48%

“…24 Titration experiments were then conducted to determine the binding constants (KD) for carboxycalixarene 1 and the small molecule binders identified by NMR. Apart from 9, which is aromatic in nature, all KD values obtained were around 60 μM with no discernible preference between dimethylammonium and trimethylammonium moieties (Table 1, Supplementary Fig.…”

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confidence: 99%

Selective recognition of the di/trimethylammonium motif by an artificial carboxycalixarene receptor

et al. 2017

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“…47,52À54 These results naturally lead us to explore whether these simple sulfonated macrocycles could bind post-translationally modified amino acids such as methylated lysines and arginines. 50 We found that 9 is very well suited to bind trimethyllysine, displaying a K d of 27.0 μM, with 70-fold selectivity over lysine, >100-fold selectivity over arginine, and even higher selectivity over all other known unmodified amino acids. 51,55 Methylation of arginine improves affinity to a lesser degree, meaning that 9 is >30-fold selective for trimethyllysine over the most highly methylated states of arginine.…”

Section: Macrocycles: Calixarenesmentioning

confidence: 97%

The Cation−π Interaction at Protein–Protein Interaction Interfaces: Developing and Learning from Synthetic Mimics of Proteins That Bind Methylated Lysines

2012

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First discovered over 60 years ago, post-translational methylation was considered an irreversible modification until the initial discoveries of demethylase enzymes in 2004. Now researchers understand that this process serves as a dynamic and complex control mechanism that is misregulated in numerous diseases. Lysine methylation is most often found on histone proteins and can effect gene regulation, epigenetic inheritance, and cancer. Because of this connection to disease, many enzymes responsible for methylation are considered targets for new cancer therapies. Although our understanding of the biology of post-translational methylation has advanced at an astonishing rate within the last 5 years, chemical approaches for studying and disrupting these pathways are only now gaining momentum. In general, enzymes methylate lysine and arginine residues with very high specificity for both the location and methylation state. Each methylated target serves as the focused hot spot for an inducible protein–protein interaction (PPI). Conceptually, lysine or arginine methylation is a subtle modification that leads to no change in charge and small changes in size, but it significantly alters the hydration energies and hydrogen bonding potential of these side chains. Nature has evolved a special motif for recognizing the methylation states of lysine, called the “aromatic cage”, a collection of aromatic protein residues, often accompanied by one or more neighboring anionic residues. The combination of favorable cation−π, electrostatic, and van der Waals interactions, as well as size matching, gives these proteins a high degree of specificity for the methylation state. This Account summarizes the development of various supramolecular host system scaffolds developed to recognize and bind to ammonium cations, such as trimethyllysine, on the basis of their methylation state. Early systems bound to their targets in pure, buffered water but failed to achieve biochemically relevant affinities and selectivities. Surprisingly, the use of the simple and very well-known p-sulfonatocalix[4]arene provides protein-like affinities and selectivities for trimethyllysine in water. New analogs, created by synthetic modification of the same scaffold, allow for further tuning of affinities and selectivities for trimethyllysine. Our studies of each family of hosts paint a consistent picture: cation−π interactions and electrostatics are important, and solvation effects are complex. Rigidity is especially important for host–guest systems that function in pure water. Despite their simplicity, synthetic systems that take these lessons into account can achieve affinities that rival or surpass those of their naturally evolved counterparts. The stage is now set for the next act: the use of such compounds as tunable and adaptable tools for modern chemical biology.

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“…25 We have previously shown that rigid, macrocyclic synthetic compounds based on para-sulfonatocalix [4]arene (PSC) are potent and selective binders of trimethyllysine as a free amino acid. 26,27 These pocket-like macrocycles bind the methylated side chain of Kme3 via multiple charge-charge and cation-pi contacts. 27 Other macrocycles can also bind Kme3 as the free amino acid 28 and within histone-tail peptide sequences 29,30 , representing an increasing interest in using structured macrocycles to target post-translational modifications directly.…”

Section: Introductionmentioning

confidence: 99%

“…26,27 These pocket-like macrocycles bind the methylated side chain of Kme3 via multiple charge-charge and cation-pi contacts. 27 Other macrocycles can also bind Kme3 as the free amino acid 28 and within histone-tail peptide sequences 29,30 , representing an increasing interest in using structured macrocycles to target post-translational modifications directly. We have also shown, using a FRETbased protein biosensor, that some simple calixarene-based agents can disrupt the interaction of H3K27me3 with CBX7.…”

Section: Introductionmentioning

confidence: 99%

Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7

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Douglas

Daze

et al. 2013

Bioorganic & Medicinal Chemistry

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A Simple Calixarene Recognizes Post‐translationally Methylated Lysine

Cited by 93 publications

References 34 publications

Selective recognition of the di/trimethylammonium motif by an artificial carboxycalixarene receptor

Selective recognition of the di/trimethylammonium motif by an artificial carboxycalixarene receptor

The Cation−π Interaction at Protein–Protein Interaction Interfaces: Developing and Learning from Synthetic Mimics of Proteins That Bind Methylated Lysines

Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7

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