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