Počet záznamů: 1
Protein-Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory
- 1.0541319 - ÚOCHB 2022 RIV US eng J - Článek v odborném periodiku
Vavřina, Zdeněk - Gutten, Ondrej - Smola, Miroslav - Zavřel, Martin - Tehrani, Zahra Aliakbar - Charvát, Vilém - Kožíšek, Milan - Bouřa, Evžen - Birkuš, Gabriel - Rulíšek, Lubomír
Protein-Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory.
Biochemistry. Roč. 60, č. 8 (2021), s. 607-620. ISSN 0006-2960. E-ISSN 1520-4995
Grant CEP: GA ČR(CZ) GA20-08772S; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: ligand-binding * STING protein * structural biology * QM/MM calculations
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 3.321, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1021/acs.biochem.0c00949
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: π-πstacking, 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 (R2 = 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.
Trvalý link: http://hdl.handle.net/11104/0318895
Počet záznamů: 1