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Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry

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Abstract

A high mobility group box 1 (HMGB1) protein has been reported to recognize both 1,2-intrastrand crosslinked DNA by cisplatin (1,2-cis-Pt-DNA) and monofunctional platinated DNA using trans-[PtCl2(NH3)(thiazole)] (1-trans-PtTz-DNA). However, the molecular basis of recognition between the trans-PtTz-DNA and HMGB1 remains unclear. In the present work, we described a hydrogen/deuterium exchange mass spectrometry (HDX-MS) method in combination with docking simulation to decipher the interactions of platinated DNA with domain A of HMGB1. The global deuterium uptake results indicated that 1-trans-PtTz-DNA bound to HMGB1a slightly tighter than the 1,2-cis-Pt-DNA. The local deuterium uptake at the peptide level revealed that the helices I and II, and loop 1 of HMGB1a were involved in the interactions with both platinated DNA adducts. However, docking simulation disclosed different H-bonding networks and distinct DNA-backbone orientations in the two Pt-DNA-HMGB1a complexes. Moreover, the Phe37 residue of HMGB1a was shown to play a key role in the recognition between HMGB1a and the platinated DNAs. In the cis-Pt-DNA-HMGB1a complex, the phenyl ring of Phe37 intercalates into a hydrophobic notch created by the two platinated guanines, while in the trans-PtTz-DNA-HMGB1a complex the phenyl ring appears to intercalate into a hydrophobic crevice formed by the platinated guanine and the opposite adenine in the complementary strand, forming a penta-layer π–π stacking associated with the adjacent thymine and the thiazole ligand. This work demonstrates that HDX-MS associated with docking simulation is a powerful tool to elucidate the interactions between platinated DNAs and proteins.

Graphical abstract: Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry

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Publication details

The article was received on 23 Jan 2017, accepted on 03 Apr 2017 and first published on 03 Apr 2017


Article type: Paper
DOI: 10.1039/C7DT00275K
Citation: Dalton Trans., 2017, Advance Article
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    Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry

    Y. Wang, Z. Du, W. Zheng, K. Wu, D. Xu, Q. Luo, Y. Zhao, J. Han, Y. Liu and F. Wang, Dalton Trans., 2017, Advance Article , DOI: 10.1039/C7DT00275K

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