Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00541558" target="_blank" >RIV/61388963:_____/21:00541558 - isvavai.cz</a>
Výsledek na webu
<a href="https://doi.org/10.1002/anie.202016805" target="_blank" >https://doi.org/10.1002/anie.202016805</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/anie.202016805" target="_blank" >10.1002/anie.202016805</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein
Popis výsledku v původním jazyce
STING (stimulator of interferon genes) is a key regulator of innate immunity that has recently been recognized as a promising drug target. STING is activated by cyclic dinucleotides (CDNs) which eventually leads to expression of type I interferons and other cytokines. Factors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs—three pairs of natural (ribo) and fluorinated (2′‐fluororibo) 3′,3′‐CDNs. X‐ray structural analyses of six {STING:CDN} complexes did not offer any explanation for the different affinities of the studied ligands. ITC showed entropy/enthalpy compensation up to 25 kcal mol−1 for this set of similar ligands. The higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropy upon binding and by smaller strain (free) energy.
Název v anglickém jazyce
Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein
Popis výsledku anglicky
STING (stimulator of interferon genes) is a key regulator of innate immunity that has recently been recognized as a promising drug target. STING is activated by cyclic dinucleotides (CDNs) which eventually leads to expression of type I interferons and other cytokines. Factors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs—three pairs of natural (ribo) and fluorinated (2′‐fluororibo) 3′,3′‐CDNs. X‐ray structural analyses of six {STING:CDN} complexes did not offer any explanation for the different affinities of the studied ligands. ITC showed entropy/enthalpy compensation up to 25 kcal mol−1 for this set of similar ligands. The higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropy upon binding and by smaller strain (free) energy.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10403 - Physical chemistry
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
Angewandte Chemie - International Edition
ISSN
1433-7851
e-ISSN
1521-3773
Svazek periodika
60
Číslo periodika v rámci svazku
18
Stát vydavatele periodika
DE - Spolková republika Německo
Počet stran výsledku
7
Strana od-do
10172-10178
Kód UT WoS článku
000631782200001
EID výsledku v databázi Scopus
2-s2.0-85103176233