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  The Molecular Tweezer CLR01 Stabilizes a Disordered Protein–Protein Interface

Bier, D., Mittal, S., Bravo-Rodriguez, K., Sowislok, A., Guillory, X., Briels, J., et al. (2017). The Molecular Tweezer CLR01 Stabilizes a Disordered Protein–Protein Interface. Journal of the American Chemical Society, 139(45), 16256-16263. doi:10.1021/jacs.7b07939.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-FC93-E Version Permalink: http://hdl.handle.net/21.11116/0000-0001-294F-A
Genre: Journal Article

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 Creators:
Bier, David1, 2, Author
Mittal, Sumit3, Author              
Bravo-Rodriguez, Kenny3, Author              
Sowislok, Andrea2, Author
Guillory, Xavier1, 2, Author
Briels, Jeroen1, 2, Author
Heid, Christian2, Author
Bartel, Maria1, Author
Wettig, Burkhard2, Author
Brunsveld, Luc1, Author
Sánchez-García, Elsa3, Author              
Schrader, Thomas2, Author
Ottmann, Christian1, 2, Author
Affiliations:
1Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands, ou_persistent22              
2Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117 Essen, Germany, ou_persistent22              
3Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              

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 Abstract: Protein regions that are involved in protein–protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein–protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular “Janus” ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein–protein interface, “freezes” one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein.

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Language(s): eng - English
 Dates: 2017-08-082017-10-172017-11-15
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1021/jacs.7b07939
 Degree: -

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Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 139 (45) Sequence Number: - Start / End Page: 16256 - 16263 Identifier: ISSN: 0002-7863
CoNE: /journals/resource/954925376870