How to deal with weak interactions in noncovalent complexes analyzed by electrospray mass spectrometry

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Author(s) Touboul, David, Maillard, Ludovic, Grässlin, Anja, Moumne, Roba, Seitz, Markus, Robinson, John, Zenobi, Renato
Publication Type Journal Items, Publication Status: Published
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Title How to deal with weak interactions in noncovalent complexes analyzed by electrospray mass spectrometry
Subtitle Cyclopeptidic inhibitors of the nuclear receptor coactivator 1-STAT6
Author(s) Touboul, David
Maillard, Ludovic
Grässlin, Anja
Moumne, Roba
Seitz, Markus
Robinson, John
Zenobi, Renato
Journal or Series Title Journal of the American Society for Mass Spectrometry
Volume Number 20
Issue Number 2
Start Page 303
End Page 311
ISSN 1044-0305
Publisher Elsevier Science
Publication Place New York, NY
Publication Date 2009
Abstract Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with KD values in the AM range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were observed by nanoelectrospray mass spectrometry, due to the use Of high ligand concentrations. Diverse strategies have already been developed to deal with nonspecific interactions, Such as controlled dissociation in the gas phase, mathematical modeling, or the use of a reference protein to monitor the appearance of nonspecific complexes. We demonstrate here that this last methodology, validated only in the case of neutral sugar-protein interactions, i.e., where dipole-dipole interactions are crucial, is not relevant in the case of strong electrostatic interactions. Thus, we developed a novel strategy based oil half-maximal inhibitory concentration (IC50) measurements in a competitive assay with readout by nanoelectrospray mass spectrometry. IC50 values determined by MS were finally converted into dissociation constants that showed very good agreement with values determined in the liquid phase using a fluorescence polarization assay.
DOI 10.1016/j.jasms.2008.10.008
Additional Notes Received 28 February 2008, Revised 2 October 2008, Accepted 6 October 2008, Available online 15 October 2008
Document Type Article
Publication Status Published
Language English
Assigned Organisational Unit(s) 03430
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NEBIS System Number 000541631
Source Database ID PP-49087
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  author = "Touboul, David and Maillard, Ludovic and Gr{\"{a}}sslin, Anja and Moumne, Roba and Seitz, Markus and Robinson, John and Zenobi, Renato",
  title = "{H}ow to deal with weak interactions in noncovalent complexes analyzed by electrospray mass spectrometry: {C}yclopeptidic inhibitors of the nuclear receptor coactivator 1-{S}{T}{A}{T}6",
  journal = "Journal of the American Society for Mass Spectrometry",
  year = 2009,
  volume = "20",
  number = "2",
  pages = "303--311",

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