Number of the records: 1
Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
- 1.
SYSNO ASEP 0549413 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations Author(s) Novotná, Barbora (UOCHB-X) ORCID
Holá, Lucie (UOCHB-X) ORCID
Staś, Monika (UOCHB-X) ORCID
Gutten, Ondrej (UOCHB-X) RID, ORCID
Smola, Miroslav (UOCHB-X) ORCID
Zavřel, Martin (UOCHB-X) ORCID
Vavřina, Zdeněk (UOCHB-X) ORCID
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Liboska, Radek (UOCHB-X) RID, ORCID
Chevrier, Florian (UOCHB-X)
Dobiaš, Juraj (UOCHB-X) ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Birkuš, Gabriel (UOCHB-X) ORCIDSource Title Biochemistry. - : American Chemical Society - ISSN 0006-2960
Roč. 60, č. 48 (2021), s. 3714-3727Number of pages 14 s. Language eng - English Country US - United States Keywords cytosolic DNA sensor ; c-di-GMP ; structural analysis OECD category Biochemistry and molecular biology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA20-08772S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000729443200005 EID SCOPUS 85119900415 DOI 10.1021/acs.biochem.1c00692 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.1021/acs.biochem.1c00692
Number of the records: 1