Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR)
Abstract The zinc transcriptional regulator (ZitR) functions as a metalloregulator that fine tunes transcriptional regulation through zinc-dependent DNA binding. However, the molecular mechanism of zinc-driven allosteric control of the DNA binding to ZitR remains elusive. Here, we performed enhanced...
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2020-08-01
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doaj-e9c7e58805aa4c4487671a6128fcfc202021-08-08T11:18:42ZengNature Publishing GroupScientific Reports2045-23222020-08-0110111210.1038/s41598-020-70381-8Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR)Xinheng He0Duan Ni1Hao Zhang2Xinyi Li3Jian Zhang4Qiang Fu5Yaqin Liu6Shaoyong Lu7Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineDepartment of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, School of MedicineMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of MedicineResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of MedicineAbstract The zinc transcriptional regulator (ZitR) functions as a metalloregulator that fine tunes transcriptional regulation through zinc-dependent DNA binding. However, the molecular mechanism of zinc-driven allosteric control of the DNA binding to ZitR remains elusive. Here, we performed enhanced sampling accelerated molecular dynamics simulations to figure out the mechanism, revealing the role of protein dynamics in the zinc-induced allosteric control of DNA binding to ZitR. The results suggest that zinc-free ZitR samples distinct conformational states, only a handful of which are compatible with DNA binding. Remarkably, zinc binding reduces the conformational plasticity of the DNA-binding domain of ZitR, promoting the population shift in the ZitR conformational ensemble towards the DNA binding-competent conformation. Further co-binding of DNA to the zinc–ZitR complex stabilizes this competent conformation. These findings suggest that ZitR–DNA interactions are allosterically regulated in a zinc-mediated conformational preselection manner, highlighting the importance of conformational dynamics in the regulation of transcription factor family.https://doi.org/10.1038/s41598-020-70381-8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xinheng He Duan Ni Hao Zhang Xinyi Li Jian Zhang Qiang Fu Yaqin Liu Shaoyong Lu |
spellingShingle |
Xinheng He Duan Ni Hao Zhang Xinyi Li Jian Zhang Qiang Fu Yaqin Liu Shaoyong Lu Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) Scientific Reports |
author_facet |
Xinheng He Duan Ni Hao Zhang Xinyi Li Jian Zhang Qiang Fu Yaqin Liu Shaoyong Lu |
author_sort |
Xinheng He |
title |
Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) |
title_short |
Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) |
title_full |
Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) |
title_fullStr |
Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) |
title_full_unstemmed |
Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR) |
title_sort |
zinc-mediated conformational preselection mechanism in the allosteric control of dna binding to the zinc transcriptional regulator (zitr) |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2020-08-01 |
description |
Abstract The zinc transcriptional regulator (ZitR) functions as a metalloregulator that fine tunes transcriptional regulation through zinc-dependent DNA binding. However, the molecular mechanism of zinc-driven allosteric control of the DNA binding to ZitR remains elusive. Here, we performed enhanced sampling accelerated molecular dynamics simulations to figure out the mechanism, revealing the role of protein dynamics in the zinc-induced allosteric control of DNA binding to ZitR. The results suggest that zinc-free ZitR samples distinct conformational states, only a handful of which are compatible with DNA binding. Remarkably, zinc binding reduces the conformational plasticity of the DNA-binding domain of ZitR, promoting the population shift in the ZitR conformational ensemble towards the DNA binding-competent conformation. Further co-binding of DNA to the zinc–ZitR complex stabilizes this competent conformation. These findings suggest that ZitR–DNA interactions are allosterically regulated in a zinc-mediated conformational preselection manner, highlighting the importance of conformational dynamics in the regulation of transcription factor family. |
url |
https://doi.org/10.1038/s41598-020-70381-8 |
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