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

Smola M, Gutten O, Dejmek M, Kožíšek M, Evangelidis T, Tehrani ZA, Novotná B, Nencka R, Birkuš G, Rulíšek L, Boura E
Angew Chem Int Ed Engl 60 10172-10178 (2021)
Related entries: 6y99, 6ydb, 6ydz, 6yea, 6z15

Cited: 7 times
EuropePMC logo PMID: 33616279

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.

Reviews - 6z0z mentioned but not cited (1)

  1. The Many Ways to Deal with STING. Coderch C, Arranz-Herrero J, Nistal-Villan E, de Pascual-Teresa B, Rius-Rocabert S. Int J Mol Sci 24 9032 (2023)

Articles - 6z0z mentioned but not cited (1)

  1. Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein. Smola M, Gutten O, Dejmek M, Kožíšek M, Evangelidis T, Tehrani ZA, Novotná B, Nencka R, Birkuš G, Rulíšek L, Boura E. Angew Chem Int Ed Engl 60 10172-10178 (2021)


Reviews citing this publication (1)

  1. Nanodelivery of STING agonists against cancer and infectious diseases. Zhou J, Ventura CJ, Fang RH, Zhang L. Mol Aspects Med 83 101007 (2022)

Articles citing this publication (4)

  1. Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists. Vavřina Z, Perlíková P, Milisavljević N, Chevrier F, Smola M, Smith J, Dejmek M, Havlíček V, Buděšínský M, Liboska R, Vaneková L, Brynda J, Boura E, Řezáčová P, Hocek M, Birkuš G. J Med Chem 65 14082-14103 (2022)
  2. Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING. Hou MH, Wang YC, Yang CS, Liao KF, Chang JW, Shih O, Yeh YQ, Sriramoju MK, Weng TW, Jeng US, Hsu SD, Chen Y. Nat Commun 14 8519 (2023)
  3. Structure of monkeypox virus poxin: implications for drug design. Duchoslav V, Boura E. Arch Virol 168 192 (2023)
  4. Research Support, Non-U.S. Gov't The Present and Future of Virology in the Czech Republic-A New Phoenix Made of Ashes? Ruml T. Viruses 14 1303 (2022)


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