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Metal binding mediated conformational change of XPA protein:a potential cytotoxic mechanism of nickel in the nucleotide excision repair

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Abstract

Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn2+-chelated Zn-finger domain of XPA center core portion (i.e., XPA98-210) is the foundation of its biological functionality, while the displacement of the Zn2+ by toxic metal ions (such as Ni2+, a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA98-210 system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA98-210 Zn-finger after the substitution of Zn2+ by Ni2+. The results showed that Ni2+ dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA98-210 with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA98-210’s Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its C-terminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni2+ disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multi-protein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni2+ binding in XPA, but may also facilitate rational anti-cancer drug design based on the NER mechanism.

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Acknowledgments

This work was supported by the funding from NIDA (P30 DA035778A1) and NIH (R01 DA025612), and in part by the National Natural Science Foundation of China (11147175, 11247018), the Key Project of Sichuan Provincial Education Bureau (12ZA066), the Project of Leshan Science and Technology Administration (14GZD022).

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    Authors and Affiliations

    1. College of Chemistry, Leshan Normal University, Leshan, Sichuan, 614004, China

      Jianping Hu

    2. Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy; NIH National Center of Excellence for Computational Drug Abuse Research; Drug Discovery Institute; Department of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA

      Jianping Hu, Ziheng Hu, Yan Zhang, Lirong Wang & Xiang-Qun Xie

    3. School of Pharmacy and Bioengineering; Key Laboratory of Medicinal and Edible Plants Resources Development, School of Bioengineering, Chengdu University, Chengdu, Sichuan, 610106, China

      Jianping Hu & Xiaojun Gou

    4. Division of Biology, Chemistry, and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA

      Ying Mu

    5. School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA

      Lirong Wang & Xiang-Qun Xie

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    Hu, J., Hu, Z., Zhang, Y. et al. Metal binding mediated conformational change of XPA protein:a potential cytotoxic mechanism of nickel in the nucleotide excision repair. J Mol Model 22, 156 (2016). https://doi.org/10.1007/s00894-016-3017-x

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