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Use of top-down and bottom-up fourier transform ion cyclotron resonance mass spectrometry for mapping calmodulin sites modified by platinum anticancer drugs
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Li, Huilin, Lin, Tzu-Yung, Van Orden, Steve L., Zhao, Yao, (Researcher in chemistry), Barrow, Mark P., Pizarro, Ana M., Qi, Yulin, Sadler, P. J. and O’Connor, Peter B. (2011) Use of top-down and bottom-up fourier transform ion cyclotron resonance mass spectrometry for mapping calmodulin sites modified by platinum anticancer drugs. Analytical Chemistry, Vol.83 (No.24). pp. 9507-9515. doi:10.1021/ac202267g ISSN 0003-2700.
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Official URL: http://dx.doi.org/10.1021/ac202267g
Abstract
Calmodulin (CaM) is a highly conserved, ubiquitous, calcium-binding protein; it binds to and regulates many different protein targets, thereby functioning as a calcium sensor and signal transducer. CaM contains 9 methionine (Met), 1 histidine (His), 17 aspartic acid (Asp), and 23 glutamine acid (Glu) residues, all of which can potentially react with platinum compounds; thus, one-third of the CaM sequence is a possible binding target of platinum anticancer drugs, which represents a major challenge for identification of specific platinum modification sites. Here, top-down electron capture dissociation (ECD) was used to elucidate the transition metal–platinum(II) modification sites. By using a combination of top-down and bottom-up mass spectrometric (MS) approaches, 10 specific binding sites for mononuclear complexes, cisplatin and [Pt(dien)Cl]Cl, and dinuclear complex [{cis-PtCl2(NH3)}2(μ-NH2(CH2)4NH2)] on CaM were identified. High resolution MS of cisplatin-modified CaM revealed that cisplatin mainly targets Met residues in solution at low molar ratios of cisplatin–CaM (2:1), by cross-linking Met residues. At a high molar ratio of cisplatin:CaM (8:1), up to 10 platinum(II) bind to Met, Asp, and Glu residues. [{cis-PtCl2(NH3)}2(μ-NH2(CH2)4NH2)] forms mononuclear adducts with CaM. The alkanediamine linker between the two platinum centers dissociates due to a trans-labilization effect. [Pt(dien)Cl]Cl forms {Pt(dien)}2+ adducts with CaM, and the preferential binding sites were identified as Met51, Met71, Met72, His107, Met109, Met124, Met144, Met145, Glu45 or Glu47, and Asp122 or Glu123. The binding of these complexes to CaM, particularly when binding involves loss of all four original ligands, is largely irreversible which could result in their failure to reach the target DNA or be responsible for unwanted side-effects during chemotherapy. Additionally, the cross-linking of cisplatin to CaM might lead to the loss of the biological function of CaM or CaM–Ca2+ due to limiting the flexibility of the CaM or CaM–Ca2+ complex to recognize target proteins or blocking the binding region of target proteins to CaM.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Engineering > Engineering |
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Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Calmodulin, Platinum compounds -- Therapeutic use, Fourier transform spectroscopy | ||||
Journal or Publication Title: | Analytical Chemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0003-2700 | ||||
Official Date: | 2011 | ||||
Dates: |
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Volume: | Vol.83 | ||||
Number: | No.24 | ||||
Page Range: | pp. 9507-9515 | ||||
DOI: | 10.1021/ac202267g | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 18 December 2015 | ||||
Date of first compliant Open Access: | 18 December 2015 | ||||
Funder: | National Institutes of Health (U.S.) (NIH), European Research Council (ERC), Engineering and Physical Sciences Research Council (EPSRC) | ||||
Grant number: | NIH/NIGMSR01GM078293 (NIH), 247450 (ERC), EP/F034210/1 (EPSRC), BP/G006792 (EPSRC) |
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