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Protein-Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory
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SYSNO ASEP 0554896 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Protein-Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory Author(s) Vavrina, Z. (CZ)
Gutten, O. (CZ)
Smola, M. (CZ)
Zavrel, M. (CZ)
Tehrani, Zahra Aliakbar (BTO-N)
Charvat, V. (CZ)
Kožíšek, M. (CZ)
Bouřa, E. (CZ)
Birkus, G. (CZ)
Rulíšek, L. (CZ)Number of authors 10 Source Title Biochemistry. - : American Chemical Society - ISSN 0006-2960
Roč. 60, č. 8 (2021), s. 607-620Number of pages 14 s. Language eng - English Country US - United States Keywords cyclic di-gmp ; interferon genes ; dna sensor ; dinucleotide Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology Method of publishing Limited access Institutional support BTO-N - RVO:86652036 UT WOS 000626270000006 EID SCOPUS 85101509244 DOI 10.1021/acs.biochem.0c00949 Annotation STING protein (stimulator of interferon genes) plays an important role in the innate immune system. A number of potent compounds regulating its activity have been reported, mostly derivatives of cyclic dinucleotides (CDNs), natural STING agonists. Here, we aim to provide complementary information to large-scale ligand-profiling studies by probing the importance of STING-CDN protein-ligand interactions on the protein side. We examined in detail six typical CDNs each in complex with 13 rationally devised mutations in STING: S162A, S162T, Y167F, G230A, R232K, R232H, A233L, A233I, R238K, T263A, T263S, R293Q, and G230A/R293Q The mutations switch on and off various types of protein-ligand interactions: pi-pi stacking, hydrogen bonding, ionic pairing, and nonpolar contacts. We correlated experimental data obtained by differential scanning fluorimetry, X-ray crystallography, and isothermal titration calorimetry with theoretical calculations. This enabled us to provide a mechanistic interpretation of the differences in the binding of representative CDNs to STING. We observed that the G230A mutation increased the thermal stability of the protein-ligand complex, indicating an increased level of ligand binding, whereas R238K and Y167F led to a complete loss of stabilization (ligand binding). The effects of the other mutations depended on the type of ligand (CDN) and varied, to some extent. A very good correlation (R-2 = 0.6) between the experimental binding affinities and interaction energies computed by quantum chemical methods enabled us to explain the effect of the studied mutations in detail and evaluate specific interactions quantitatively. Our work may inspire development of high-affinity ligands against the common STING haplotypes by targeting the key (sometimes non-intuitive) protein-ligand interactions. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2022 Electronic address https://pubs.acs.org/doi/10.1021/acs.biochem.0c00949
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