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How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency
- Source :
- Journal of Chemical Information and Modeling, Journal of Chemical Information and Modeling, 2022, 62 (12), pp.3096-3106. ⟨10.1021/acs.jcim.2c00315⟩
- Publication Year :
- 2022
-
Abstract
- The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue…), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.
- Subjects :
- General Chemical Engineering
Population
Library and Information Sciences
Biology
Proinflammatory cytokine
mutation
Immune system
[CHIM]Chemical Sciences
Humans
education
Pathogen
wild-type
education.field_of_study
Wild type
Membrane Proteins
General Chemistry
STING protein
Immunity, Innate
Computer Science Applications
Sting
molecular dynamics simulation
Settore CHIM/03 - Chimica Generale E Inorganica
Stimulator of interferon genes
Immunology
Interferons
Signal transduction
Subjects
Details
- ISSN :
- 1549960X and 15499596
- Volume :
- 62
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Journal of chemical information and modeling
- Accession number :
- edsair.doi.dedup.....853a524e103e7158027851467c6ff409