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Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein
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SYSNO ASEP 0556414 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein Author(s) Aliakbar Tehrani, Zahra (BTO-N)
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Černý, Jiří (BTO-N) RID, ORCIDNumber of authors 3 Article number 2021-07-12 Source Title Journal of Biomolecular Structure & Dynamics. - : Taylor & Francis - ISSN 0739-1102
JUN 2021, JUN 2021 (2021)Number of pages 16 s. Language eng - English Country US - United States Keywords NETWORK ANALYSIS ; INTERFERON GENES ; LIGAND ; RECOGNITION Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects EF16_013/0001777 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018131 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001776 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA20-08772S GA ČR - Czech Science Foundation (CSF) Research Infrastructure CESNET II - 90042 - CESNET - zájmové sdružení právnických osob Method of publishing Limited access Institutional support BTO-N - RVO:86652036 ; UOCHB-X - RVO:61388963 UT WOS 000668459800001 EID SCOPUS 85109015815 DOI 10.1080/07391102.2021.1942213 Annotation Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3 '-3 ', 2 '-2 ' or mixed 2 '-3 '-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTING(wt) protein. Our results revealed that CDN/hSTING(wt) interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTING(wt) ligand binding cavity, especially in alpha(1)-helices, the so-called lid region and alpha(2)-tails. The ligand residence time in hSTING(wt) protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTING(wt) protein. These findings may perhaps guide design of new compounds modulating hSTING activity. Communicated by Ramaswamy H. Sarma Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2022 Electronic address https://www.tandfonline.com/doi/full/10.1080/07391102.2021.1942213
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