Direct monitoring of protein-protein inhibition using nano electrospray ionization mass spectrometry

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Author(s) Cubrilovic, Dragana, Barylyuk, Konstantin, Hofmann, Daniela, Walczak, Michal J., Gräber, Martin, Berg, Thorsten, Wider, Gerhard, Zenobi, Renato
Publication Type Journal Items, Publication Status: Published
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Title Direct monitoring of protein-protein inhibition using nano electrospray ionization mass spectrometry
Author(s) Cubrilovic, Dragana
Barylyuk, Konstantin
Hofmann, Daniela
Walczak, Michal J.
Gräber, Martin
Berg, Thorsten
Wider, Gerhard
Zenobi, Renato
Journal or Series Title Chemical science
Volume Number 5
Issue Number 7
Start Page 2794
End Page 2803
ISSN 2041-6520
Publisher Royal Society of Chemistry
Publication Place Cambridge
Publication Date 2014-07
Abstract Dissociation of the TNF-alpha trimer caused by the small-molecule inhibitor SPD304 was monitored using native ESI-MS and ion mobility spectrometry (IMS). Upon addition of the inhibitor, our data clearly indicate partial dissociation of the protein into dimers and monomers. The IMS-MS analysis shows that dimeric ions have their own characteristic drift time distributions, which are different from those of the dimer ions originating in the gas phase due to collision-induced dissociation. We show that only one equivalent of the inhibitor binds to the trimeric form. We also investigated inhibition of heterodimer formation of the survival protein Bcl-xL with the cell death-promoting regions of the proteins Bak and Bad, using the small inhibitors ABT737 and ABT263. We found that ABT737 is more potent than ABT263 in preventing the heterodimerization between Bcl-xL and the Bak and Bad derived BH3 peptides. We could also monitor the mode of binding, which in this case is competitive. These results indicate that native ESI-MS can be widely used to study the inhibition of other relevant protein–protein interactions (PPIs), and provide a good basis for further improvement and identification of small-molecule PPI inhibitors.
DOI 10.1039/c3sc53360c
Additional Notes Received 7 December 2013, Accepted 18 March 2014, First published online 18 March 2014
Document Type Article
Publication Status Published
Language English
Assigned Organisational Unit(s) 08794
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NEBIS System Number 006104946
Source Database ID SCOPUS-84901826827
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  author = "Cubrilovic, Dragana and Barylyuk, Konstantin and Hofmann, Daniela and Walczak, Michal J. and Gr{\"{a}}ber, Martin and Berg, Thorsten and Wider, Gerhard and Zenobi, Renato",
  title = "{D}irect monitoring of protein-protein inhibition using nano electrospray ionization mass spectrometry",
  journal = "Chemical science",
  year = 2014,
  volume = "5",
  number = "7",
  pages = "2794--2803",
  month = jul,

E-Citations record created: Tue, 24 Jun 2014, 07:49:27 CET