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Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F21%3A00556414" target="_blank" >RIV/86652036:_____/21:00556414 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/61388963:_____/21:00556414

  • Výsledek na webu

    <a href="https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1942213" target="_blank" >https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1942213</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1080/07391102.2021.1942213" target="_blank" >10.1080/07391102.2021.1942213</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

  • Popis výsledku v původním jazyce

    Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3 '-3 ', 2 '-2 ' or mixed 2 '-3 '-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTING(wt) protein. Our results revealed that CDN/hSTING(wt) interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTING(wt) ligand binding cavity, especially in alpha(1)-helices, the so-called lid region and alpha(2)-tails. The ligand residence time in hSTING(wt) protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTING(wt) protein. These findings may perhaps guide design of new compounds modulating hSTING activity. Communicated by Ramaswamy H. Sarma

  • Název v anglickém jazyce

    Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

  • Popis výsledku anglicky

    Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3 '-3 ', 2 '-2 ' or mixed 2 '-3 '-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTING(wt) protein. Our results revealed that CDN/hSTING(wt) interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTING(wt) ligand binding cavity, especially in alpha(1)-helices, the so-called lid region and alpha(2)-tails. The ligand residence time in hSTING(wt) protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTING(wt) protein. These findings may perhaps guide design of new compounds modulating hSTING activity. Communicated by Ramaswamy H. Sarma

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

    Journal of Biomolecular Structure & Dynamics

  • ISSN

    0739-1102

  • e-ISSN

  • Svazek periodika

    JUN 2021

  • Číslo periodika v rámci svazku

    JUN 2021

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    16

  • Strana od-do

    2021-07-12

  • Kód UT WoS článku

    000668459800001

  • EID výsledku v databázi Scopus

    2-s2.0-85109015815