Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein. Issue 18 (24th March 2021)

• Record Type: Journal Article
• Authors: Smola, Miroslav; Gutten, Ondrej; Dejmek, Milan; Kožíšek, Milan; Evangelidis, Thomas; Tehrani, Zahra Aliakbar; Novotná, Barbora; Nencka, Radim; Birkuš, Gabriel; Rulíšek, Lubomír; Boura, Evzen
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 18(2021)
• Page Start: 10172
• Page End: 10178
• Publication Date: 2021-03-24
• Subjects: conformational analysis -- cyclic dinucleotides -- entropy -- quantum chemistry -- strain energy; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202016805
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : The complexity of the thermodynamics associated with the binding of fluorinated and non‐fluorinated cyclic dinucleotides to the STING protein was analyzed and explained by employing a combination of experimental and theoretical methods. Large enthalpy/entropy compensations can only be explained by complementing the structural and energetic analysis of the complex with conformational analysis of free ligands.