scholarly journals Probing the Binding Requirements of Modified Nucleosides with the DNA Nuclease SNM1A

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 320
Author(s):  
Eva-Maria Dürr ◽  
Joanna F. McGouran
Keyword(s):  
Metal Binding ◽  
Metal Ion ◽  
Hydroxamic Acid ◽  
Inhibitory Effect ◽  
Modified Nucleosides ◽  
Interstrand Crosslink ◽  
Close Proximity ◽  
Interstrand Crosslink Repair ◽  
Crosslinking Agents ◽  
Charged Group

SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.

Structures of c-di-GMP/cGAMP degrading phosphodiesterase VcEAL: identification of a novel conformational switch and its implication

2019 ◽  
Vol 476 (21) ◽  
pp. 3333-3353 ◽  
Author(s):  
Malti Yadav ◽  
Kamalendu Pal ◽  
Udayaditya Sen
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Triosephosphate Isomerase ◽  
Catalytic Mechanism ◽  
Degradation Mechanism ◽  
Structural Basis ◽  
Conserved Residues ◽  
Phosphodiester Bond ◽  
Cyclic Dinucleotides

Cyclic dinucleotides (CDNs) have emerged as the central molecules that aid bacteria to adapt and thrive in changing environmental conditions. Therefore, tight regulation of intracellular CDN concentration by counteracting the action of dinucleotide cyclases and phosphodiesterases (PDEs) is critical. Here, we demonstrate that a putative stand-alone EAL domain PDE from Vibrio cholerae (VcEAL) is capable to degrade both the second messenger c-di-GMP and hybrid 3′3′-cyclic GMP–AMP (cGAMP). To unveil their degradation mechanism, we have determined high-resolution crystal structures of VcEAL with Ca2+, c-di-GMP-Ca2+, 5′-pGpG-Ca2+ and cGAMP-Ca2+, the latter provides the first structural basis of cGAMP hydrolysis. Structural studies reveal a typical triosephosphate isomerase barrel-fold with substrate c-di-GMP/cGAMP bound in an extended conformation. Highly conserved residues specifically bind the guanine base of c-di-GMP/cGAMP in the G2 site while the semi-conserved nature of residues at the G1 site could act as a specificity determinant. Two metal ions, co-ordinated with six stubbornly conserved residues and two non-bridging scissile phosphate oxygens of c-di-GMP/cGAMP, activate a water molecule for an in-line attack on the phosphodiester bond, supporting two-metal ion-based catalytic mechanism. PDE activity and biofilm assays of several prudently designed mutants collectively demonstrate that VcEAL active site is charge and size optimized. Intriguingly, in VcEAL-5′-pGpG-Ca2+ structure, β5–α5 loop adopts a novel conformation that along with conserved E131 creates a new metal-binding site. This novel conformation along with several subtle changes in the active site designate VcEAL-5′-pGpG-Ca2+ structure quite different from other 5′-pGpG bound structures reported earlier.

scholarly journals Acylated Anthocyanins from Red Cabbage and Purple Sweet Potato Can Bind Metal Ions and Produce Stable Blue Colors

2021 ◽  
Vol 22 (9) ◽  
pp. 4551
Author(s):  
Julie-Anne Fenger ◽  
Gregory T. Sigurdson ◽  
Rebecca J. Robbins ◽  
Thomas M. Collins ◽  
M. Mónica Giusti ◽  
...  
Keyword(s):  
Metal Ions ◽  
Sweet Potato ◽  
Metal Binding ◽  
Metal Ion ◽  
High Resolution Mass Spectrometry ◽  
Large Set ◽  
Water Addition ◽  
Red Cabbage ◽  
Aluminum Ions ◽  
Purple Sweet Potato

Red cabbage (RC) and purple sweet potato (PSP) are naturally rich in acylated cyanidin glycosides that can bind metal ions and develop intramolecular π-stacking interactions between the cyanidin chromophore and the phenolic acyl residues. In this work, a large set of RC and PSP anthocyanins was investigated for its coloring properties in the presence of iron and aluminum ions. Although relatively modest, the structural differences between RC and PSP anthocyanins, i.e., the acylation site at the external glucose of the sophorosyl moiety (C2-OH for RC vs. C6-OH for PSP) and the presence of coordinating acyl groups (caffeoyl) in PSP anthocyanins only, made a large difference in the color expressed by their metal complexes. For instance, the Al3+-induced bathochromic shifts for RC anthocyanins reached ca. 50 nm at pH 6 and pH 7, vs. at best ca. 20 nm for PSP anthocyanins. With Fe2+ (quickly oxidized to Fe3+ in the complexes), the bathochromic shifts for RC anthocyanins were higher, i.e., up to ca. 90 nm at pH 7 and 110 nm at pH 5.7. A kinetic analysis at different metal/ligand molar ratios combined with an investigation by high-resolution mass spectrometry suggested the formation of metal–anthocyanin complexes of 1:1, 1:2, and 1:3 stoichiometries. Contrary to predictions based on steric hindrance, acylation by noncoordinating acyl residues favored metal binding and resulted in complexes having much higher molar absorption coefficients. Moreover, the competition between metal binding and water addition to the free ligands (leading to colorless forms) was less severe, although very dependent on the acylation site(s). Overall, anthocyanins from purple sweet potato, and even more from red cabbage, have a strong potential for development as food colorants expressing red to blue hues depending on pH and metal ion.

scholarly journals Crystallographic and X-ray absorption spectroscopic characterization of Helicobacter pylori UreE bound to Ni2+ and Zn2+ reveals a role for the disordered C-terminal arm in metal trafficking

2012 ◽  
Vol 441 (3) ◽  
pp. 1017-1035 ◽  
Author(s):  
Katarzyna Banaszak ◽  
Vlad Martin-Diaconescu ◽  
Matteo Bellucci ◽  
Barbara Zambelli ◽  
Wojciech Rypniewski ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Metal Ions ◽  
Metal Binding ◽  
Metal Ion ◽  
Mutual Influence ◽  
Accurate Information ◽  
Metal Ion Binding ◽  
X Ray ◽  
X Ray Absorption

The survival and growth of the pathogen Helicobacter pylori in the gastric acidic environment is ensured by the activity of urease, an enzyme containing two essential Ni2+ ions in the active site. The metallo-chaperone UreE facilitates in vivo Ni2+ insertion into the apoenzyme. Crystals of apo-HpUreE (H. pylori UreE) and its Ni2+- and Zn2+-bound forms were obtained from protein solutions in the absence and presence of the metal ions. The crystal structures of the homodimeric protein, determined at 2.00 Å (apo), 1.59 Å (Ni2+) and 2.52 Å (Zn2+) resolution, show the conserved proximal and solvent-exposed His102 residues from two adjacent monomers invariably involved in metal binding. The C-terminal regions of the apoprotein are disordered in the crystal, but acquire significant ordering in the presence of the metal ions due to the binding of His152. The analysis of X-ray absorption spectral data obtained using solutions of Ni2+- and Zn2+-bound HpUreE provided accurate information of the metal-ion environment in the absence of solid-state effects. These results reveal the role of the histidine residues at the protein C-terminus in metal-ion binding, and the mutual influence of protein framework and metal-ion stereo-electronic properties in establishing co-ordination number and geometry leading to metal selectivity.

scholarly journals RNF138 interacts with RAD51D and is required for DNA interstrand crosslink repair and maintaining chromosome integrity

DNA Repair ◽  
2016 ◽  
Vol 42 ◽  
pp. 82-93 ◽  
Author(s):  
Brian D. Yard ◽  
Nicole M. Reilly ◽  
Michael K. Bedenbaugh ◽  
Douglas L. Pittman
Keyword(s):  
Interstrand Crosslink ◽  
Chromosome Integrity ◽  
Interstrand Crosslink Repair ◽  
Crosslink Repair

scholarly journals BRCA1 Functions Independently of Homologous Recombination in DNA Interstrand Crosslink Repair

2012 ◽  
Vol 46 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Samuel F. Bunting ◽  
Elsa Callén ◽  
Marina L. Kozak ◽  
Jung Min Kim ◽  
Nancy Wong ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Interstrand Crosslink ◽  
Interstrand Crosslink Repair ◽  
Crosslink Repair

scholarly journals Mechanism of Replication-Coupled DNA Interstrand Crosslink Repair

Cell ◽  
2009 ◽  
Vol 137 (5) ◽  
pp. 972 ◽  
Author(s):  
Markus Räschle ◽  
Puck Knipscheer ◽  
Milica Enoiu ◽  
Todor Angelov ◽  
Jingchuan Sun ◽  
...  
Keyword(s):  
Interstrand Crosslink ◽  
Interstrand Crosslink Repair ◽  
Crosslink Repair

Metal ion – biomolecule interactions. X. Synthesis, spectroscopic and magnetic resonance investigations of methylmercury(II) complexes of the sulfur modified nucleosides 6- mercaptopurine riboside and 2-amino-6-mercaptopurine riboside

1986 ◽  
Vol 64 (3) ◽  
pp. 442-448 ◽  
Author(s):  
E. Buncel ◽  
R. Kumar ◽  
A. R. Norris
Keyword(s):  
Aqueous Solution ◽  
Metal Ion ◽  
Chemotherapeutic Agents ◽  
Modified Nucleosides ◽  
Coupling Constants ◽  
Heterocyclic Ligands ◽  
Methylmercury Poisoning ◽  
Insight Into ◽  
C Nmr ◽  
Ligand Bond

A number of methylmercurated complexes of 6-mercaptopurine riboside and 2-amino-6-mercaptopurine riboside (6-MNucH2) containing S-bound CH3Hg(II) in neutral and cationic complexes (as in [CH3Hg(6-MNucH)] and [CH3Hg(6-MNucH2)]NO3), S- and N-bound CH3Hg(II) (as in [(CH3Hg)2(6-MNucH)]NO3), and S-, N-, C-bound CH3Hg(II) (as in [(CH3Hg)3(6-MNuc)]NO3) have been prepared in aqueous solution at appropriate pH and mole ratios of the constituents. The complexes were characterized by means of 1H and 13C nmr and ir spectroscopy and elemental analysis. Formation of C-bound methylmercurated species extends our previous results obtained with xanthosine, inosine, and imidazole derivatives, and substantiates our proposal that activation through electrophilic coordination at N(7) is a requirement for C(8)—H abstraction. 2J(1H–199Hg) coupling constants, measured in (CD3)2SO for a number of CH3Hg(II) complexes of N-, S-, and C-donor heterocyclic ligands, including the 6-mercaptopurine riboside of the present study, correlate well with the 1J(13C–199Hg) coupling constants, according to 1J = 8.4602J − 155.6. The significance of this correlation in terms of the strength of the Hg–ligand bond is considered. The results could provide insight into the apparent selectivity of binding of CH3Hg(II) by bio-ligands, as well as in the design of chemotherapeutic agents for the treatment of methylmercury poisoning.

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