Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein
| Autor: | Miroslav Smola, Ondrej Gutten, Milan Dejmek, Milan Kožíšek, Thomas Evangelidis, Zahra Aliakbar Tehrani, Barbora Novotná, Radim Nencka, Gabriel Birkuš, Lubomír Rulíšek, Evzen Boura |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Stereochemistry Ligand Binding Molecular Conformation Ligands 010402 general chemistry 01 natural sciences Catalysis quantum chemistry Humans strain energy Research Articles Binding Sites Strain (chemistry) 010405 organic chemistry Chemistry conformational analysis Membrane Proteins Isothermal titration calorimetry General Medicine General Chemistry Ligand (biochemistry) Affinities 0104 chemical sciences Sting Structural biology Stimulator of interferon genes Nucleotides Cyclic entropy Research Article cyclic dinucleotides Entropy (order and disorder) |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202016805 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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