Spectrometric Studies of Nucleic Acid Derivatives and Related Compounds. VI. On the Structure of Certain 5- and 6-Halogenouracils and -cytosines

Wempen, Iris; Fox, Jack J.

doi:10.1021/ja01066a034

Cited by 88 publications

(38 citation statements)

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“…However, the charge state of the ring depends upon the pK a of the uracil ring and the pH of the solution. For IW and FW, the pK a is well above the pH (8.25 and 8, respectively) (26), so the NH of the ring is largely protonated. In these cases, the amide protons of Glu-705 and Thr-655 exchange rapidly before the first spectrum is taken at 10°C.…”

Section: Resultsmentioning

confidence: 98%

Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Ahmed¹,

Ptak²,

Fenwick

et al. 2013

Journal of Biological Chemistry

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Background: Glutamate receptors are essential proteins for transmitting information in the CNS. Results: The stability of H-bonds at multiple points within the ligand-binding domain varies with the efficacy of the bound agonist. Conclusion: H-bonds inside and outside of the binding pocket contribute to channel activation and desensitization. Significance: Fine-tuning of glutamate receptor responses is dependent upon electrostatic interactions and H-bonds outside of the binding pocket.

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Section: Resultsmentioning

confidence: 98%

Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Ahmed¹,

Ptak²,

Fenwick

et al. 2013

Journal of Biological Chemistry

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“…While the 5-Br substituent enhances leaving-group quality by increasing N1 acidity (Δp K a N1 = −2), it also increases N3 acidity (Δp K a N3 = 1.6) such that such that acid catalysis is less effective. 92, 93 Thus, leaving-group quality is better for 5-Br-C versus C, but dC is hydrolyzed as rapidly as 5-Br-dC (95 °C, pH 5) because acid catalysis is more effective for dC than 5-Br-dC. The effect of electron-withdrawing substituents on acidity (N1, N3) and glycosidic bond hydrolysis for dC analogues is an important factor when considering the enzymatic removal of the oxidized forms of 5-methylcytosine found in mammalian DNA, as discussed below.…”

Section: Role Of the Leaving Groupmentioning

confidence: 99%

Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA

Drohat

Maiti

2014

Org. Biomol. Chem.

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DNA glycosylases remove damaged or enzymatically modified nucleobases from DNA, thereby initiating the base excision repair (BER) pathway, which is found in all forms of life. These ubiquitous enzymes promote genomic integrity by initiating repair of mutagenic and/or cytotoxic lesions that arise continuously due to alkylation, deamination, or oxidation of the normal bases in DNA. Glycosylases also perform essential roles in epigenetic regulation of gene expression, by targeting enzymatically-modified forms of the canonical DNA bases. Monofunctional DNA glycosylases hydrolyze the N-glycosidic bond to liberate the target base, while bifunctional glycosylases mediate glycosyl transfer using an amine group of the enzyme, generating a Schiff base intermediate that facilitates their second activity, cleavage of the DNA backbone. Here we review recent advances in understanding the chemical mechanism of monofunctional DNA glycosylases, with an emphasis on how the reactions are influenced by properties of the nucleobase leaving-group, the moiety that varies across the vast range of substrates targeted by these enzymes.

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“…20,[32][33][34] Substitution of hydrogen with more strongly electronegative halogens at the 5-position of the ring decreases the ligand pK a for deprotonation at the 3-position and increases ligand potency and binding affinity for AMPA receptors in the order HW b IW b BrW b FW. 20,[32][33][34][35][36] In contrast, the peak current and extent of receptor desensitization vary according to the size of the 5-position substituent as IW b BrW b FW b HW. 20,32,33 Insights into the structural basis of the latter trend were gained from the determination of several crystal structures of S1S2 complexes with willardiine derivatives.…”

Section: Introductionmentioning

confidence: 99%

NMR Spectroscopy of the Ligand-Binding Core of Ionotropic Glutamate Receptor 2 Bound to 5-Substituted Willardiine Partial Agonists

Fenwick

Oswald

2008

Journal of Molecular Biology

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Glutamate receptors mediate neuronal intercommunication in the central nervous system by coupling extracellular neurotransmitter-receptor interactions to ion channel conductivity. To gain insight into structural and dynamical factors that underlie this coupling, solution NMR experiments were performed on the bilobed ligand-binding core of glutamate receptor 2 in complexes with a set of willardiine partial agonists. These agonists are valuable for studying structure-function relationships because their 5-position substituent size is correlated with ligand efficacy and extent of receptor desensitization, whereas the substituent electronegativity is correlated with ligand potency. NMR results show that the protein backbone amide chemical shift deviations correlate mainly with efficacy and extent of desensitization. Pronounced deviations occur at specific residues in the ligand-binding site and in the two helical segments that join the lobes by a disulfide bond. Experiments detecting conformational exchange show that micro- to millisecond timescale motions also occur near the disulfide bond and vary largely with efficacy and extent of desensitization. These results thus identify regions displaying structural and dynamical dissimilarity arising from differences in ligand-protein interactions and lobe closure that may play a critical role in receptor response. Furthermore, measures of line broadening and conformational exchange for a portion of the ligand-binding site correlate with ligand EC(50) data. These results do not have any correlate in the currently available crystal structures and thus provide a novel view of ligand-binding events that may be associated with agonist potency differences.

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Spectrometric Studies of Nucleic Acid Derivatives and Related Compounds. VI. On the Structure of Certain 5- and 6-Halogenouracils and -cytosines

Cited by 88 publications

References 0 publications

Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA

NMR Spectroscopy of the Ligand-Binding Core of Ionotropic Glutamate Receptor 2 Bound to 5-Substituted Willardiine Partial Agonists

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