Single Mutations Reshape the Structural Correlation Network of the DMXAA-Human STING Complex.
Subtle changes in protein sequences are able to alter ligand-protein interactions. Unraveling the mechanism of such phenomena is important for understanding ligand-protein interactions, including the DMXAA-STING interaction. DMXAA specifically binds to mouse STING instead of human STING. However, the S162A mutation and a newly discovered E260I mutation endow human STINGAQwith DMXAA sensitivity. Through molecular dynamics simulations, we revealed how these single mutations alter the DMXAA-STING interaction. Compared to mutated systems, structural correlations in the interaction of STINGAQwith DMXAA are stronger, and the correlations are cross-protomers in the dimeric protein. Analyses on correlation coefficients lead to the identification of two key interactions that mediate the strong cross-protomer correlation in the DMXAA-STINGAQinteraction network: DMXAA-267T-162S* and 238R-260E*. These two interactions are partially and totally interrupted by the S162A and E260I mutations, respectively. Moreover, a smaller number of water molecules are displaced upon DMXAA binding to STINGAQthan that on binding to its mutants, leading to a larger entropic penalty for the former. Considering the sensitivity of STINGAQand two of its mutants to DMXAA, a strong structural correlation appears to discourage DMXAA-STING binding. Such an observation suggests that DMXAA derivatives, which are deprived of hydrogen-bond interaction with both 162S* and 267T, are potential agonists of human STING.
Institute 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.
Xing
X
Che
Institute 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.
Xiao-Xia
XX
Du
Institute 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.
Xiaoxia
X
Cai
Institute 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.
Jun
J
Zhang
Institute 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.
Wen Jun
WJ
Xie
Institute 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.
Zhuoran
Z
Long
Institute 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.
Zhao-Yang
ZY
Ye
Institute 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.
Heng
H
Zhang
Institute 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.
Lijiang
L
Yang
Institute 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.
Xiao-Dong
XD
Su
Institute 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.
Yi Qin
0000-0002-4309-9376
YQ
Gao
D019277:Entropy; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D044004:Xanthones / Q000737:chemistry*; D000099197:STING Protein
D008565:Membrane Proteins; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C066668:vadimezan