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Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

Identifikátory výsledku

  • Kód výsledku v 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>

  • Nalezeny alternativní kódy

    RIV/00216208:11310/21:10437470

  • Výsledek na webu

    <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>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

  • Popis výsledku v původním jazyce

    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.

  • Název v anglickém jazyce

    Enzymatic Synthesis of 3′-5′, 3′-5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

  • Popis výsledku anglicky

    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.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10608 - Biochemistry and molecular biology

Návaznosti výsledku

  • Projekt

    Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Ostatní

  • Rok uplatnění

    2021

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Biochemistry

  • ISSN

    0006-2960

  • e-ISSN

  • Svazek periodika

    60

  • Číslo periodika v rámci svazku

    48

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    14

  • Strana od-do

    3714-3727

  • Kód UT WoS článku

    000729443200005

  • EID výsledku v databázi Scopus

    2-s2.0-85119900415