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Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein
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SYSNO ASEP 0541558 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein Author(s) Smola, Miroslav (UOCHB-X) ORCID
Gutten, Ondrej (UOCHB-X) RID, ORCID
Dejmek, Milan (UOCHB-X) RID, ORCID
Kožíšek, Milan (UOCHB-X) RID, ORCID
Evangelidis, Thomas (UOCHB-X) ORCID
Tehrani, Zahra Aliakbar (UOCHB-X) ORCID
Novotná, Barbora (UOCHB-X) ORCID
Nencka, Radim (UOCHB-X) RID, ORCID
Birkuš, Gabriel (UOCHB-X) ORCID
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Bouřa, Evžen (UOCHB-X) ORCIDSource Title Angewandte Chemie - International Edition. - : Wiley - ISSN 1433-7851
Roč. 60, č. 18 (2021), s. 10172-10178Number of pages 7 s. Language eng - English Country DE - Germany Keywords conformational analysis ; cyclic dinucleotides ; entropy ; quantum chemistry ; strain energy OECD category Physical chemistry R&D Projects GA20-08772S GA ČR - Czech Science Foundation (CSF) EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure e-INFRA CZ - 90140 - CESNET, zájmové sdružení právnických osob Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000631782200001 EID SCOPUS 85103176233 DOI 10.1002/anie.202016805 Annotation 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. 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/10.1002/anie.202016805
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