Single Mutations Reshape the Structural Correlation Network of the DMXAA-Human STING Complex.
Xing Che1, Xiao-Xia Du1, Xiaoxia Cai1
1Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and Biodynamic Optical Imaging Center and ‡State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center, School of Life Sciences, Peking University , Beijing 100871, China.
The Journal of Physical Chemistry. B
|February 9, 2017
Summary
Single mutations in human STING (stimulator of interferon genes) can enable binding to DMXAA. Molecular dynamics revealed that strong structural correlations in STING hinder DMXAA binding, suggesting new drug design strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Ligand-protein interactions are crucial for biological processes.
- The DMXAA-STING interaction is a key area of research.
- Human STING typically does not bind DMXAA, unlike mouse STING.
Purpose of the Study:
- To investigate how single amino acid mutations in human STING affect DMXAA binding.
- To elucidate the molecular mechanisms underlying altered DMXAA-STING interactions.
- To identify potential strategies for developing human STING agonists.
Main Methods:
- Molecular dynamics simulations were employed to analyze the DMXAA-STING interaction.
- Analysis of structural correlations and interaction networks.
- Assessment of water molecule displacement and entropic penalties upon ligand binding.
Main Results:
- Single mutations (S162A and E260I) confer DMXAA sensitivity to human STINGAQ.
- Stronger cross-protomer structural correlations were observed in STINGAQ compared to mutants.
- Key interactions (DMXAA-267T-162S* and 238R-260E*) were identified and shown to be disrupted by mutations.
- DMXAA binding to STINGAQ resulted in a smaller entropic penalty compared to mutants.
Conclusions:
- Strong structural correlations in the DMXAA-STINGAQ interaction network appear to impede ligand binding.
- The S162A and E260I mutations alter these correlations, enabling DMXAA sensitivity.
- DMXAA derivatives lacking specific hydrogen-bond interactions may act as agonists for human STING.
