Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein

0541558 - ÚOCHB 2022 RIV DE eng J - Článek v odborném periodiku
Smola, Miroslav - Gutten, Ondrej - Dejmek, Milan - Kožíšek, Milan - Evangelidis, Thomas - Tehrani, Zahra Aliakbar - Novotná, Barbora - Nencka, Radim - Birkuš, Gabriel - Rulíšek, Lubomír - Bouřa, Evžen
Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein.
Angewandte Chemie - International Edition. Roč. 60, č. 18 (2021), s. 10172-10178. ISSN 1433-7851. E-ISSN 1521-3773
Grant CEP: GA ČR(CZ) GA20-08772S; GA MŠMT(CZ) EF16_019/0000729
Výzkumná infrastruktura: e-INFRA CZ - 90140
Institucionální podpora: RVO:61388963
Klíčová slova: conformational analysis * cyclic dinucleotides * entropy * quantum chemistry * strain energy
Obor OECD: Physical chemistry
Impakt faktor: 16.823, rok: 2021
Způsob publikování: Open access
https://doi.org/10.1002/anie.202016805

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.
Trvalý link: http://hdl.handle.net/11104/0319101