Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00549413" target="_blank" >RIV/61388963:_____/21:00549413 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/21:10437470
Result on the web
<a href="https://doi.org/10.1021/acs.biochem.1c00692" target="_blank" >https://doi.org/10.1021/acs.biochem.1c00692</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.biochem.1c00692" target="_blank" >10.1021/acs.biochem.1c00692</a>
Alternative languages
Result language
angličtina
Original language name
Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
Original language description
The 3′–5′, 3′–5′ cyclic dinucleotides (3′3′CDNs) are bacterial second messengers that can also bind to the stimulator of interferon genes (STING) adaptor protein in vertebrates and activate the host innate immunity. Here, we profiled the substrate specificity of four bacterial dinucleotide synthases from Vibrio cholerae (DncV), Bacillus thuringiensis (btDisA), Escherichia coli (dgcZ), and Thermotoga maritima (tDGC) using a library of 33 nucleoside-5′-triphosphate analogues and then employed these enzymes to synthesize 24 3′3′CDNs. The STING affinity of CDNs was evaluated in cell-based and biochemical assays, and their ability to induce cytokines was determined by employing human peripheral blood mononuclear cells. Interestingly, the prepared heterodimeric 3′3′CDNs bound to the STING much better than their homodimeric counterparts and showed similar or better potency than bacterial 3′3′CDNs. We also rationalized the experimental findings by in-depth STING-CDN structure–activity correlations by dissecting computed interaction free energies into a set of well-defined and intuitive terms. To this aim, we employed state-of-the-art methods of computational chemistry, such as quantum mechanics/molecular mechanics (QM/MM) calculations, and complemented the computed results with the {STING:3′3′c-di-ara-AMP} X-ray crystallographic structure. QM/MM identified three outliers (mostly homodimers) for which we have no clear explanation of their impaired binding with respect to their heterodimeric counterparts, whereas the R2 = 0.7 correlation between the computed ΔG′int_rel and experimental ΔTm’s for the remaining ligands has been very encouraging.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochemistry
ISSN
0006-2960
e-ISSN
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Volume of the periodical
60
Issue of the periodical within the volume
48
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
3714-3727
UT code for WoS article
000729443200005
EID of the result in the Scopus database
2-s2.0-85119900415