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  A designed conformational shift to control protein binding specificity.

Michielssens, S., Peters, J. H., Ban, D., Pratihar, S., Seeliger, D., Sharma, M., et al. (2014). A designed conformational shift to control protein binding specificity. Angewandte Chemie International Edition, 53(39), 10367-10371. doi:10.1002/anie.201403102.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-282F-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CDE6-7
Genre: Journal Article

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 Creators:
Michielssens, S.1, Author              
Peters, J. H.1, Author              
Ban, D.2, Author              
Pratihar, S.2, Author              
Seeliger, D.1, Author              
Sharma, M.1, Author              
Giller, K.2, Author              
Sabo, T. M.2, Author              
Becker, S.2, Author              
Lee, D.2, Author              
Griesinger, C.2, Author              
de Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578573              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: molecular dynamics; protein design; protein–protein interactions; ubiquitin
 Abstract: In a conformational selection scenario, manipulating the populations of binding-competent states should be expected to affect protein binding. We demonstrate how in silico designed point mutations within the core of ubiquitin, remote from the binding interface, change the binding specificity by shifting the conformational equilibrium of the ground-state ensemble between open and closed substates that have a similar population in the wild-type protein. Binding affinities determined by NMR titration experiments agree with the predictions, thereby showing that, indeed, a shift in the conformational equilibrium enables us to alter ubiquitin’s binding specificity and hence its function. Thus, we present a novel route towards designing specific binding by a conformational shift through exploiting the fact that conformational selection depends on the concentration of binding-competent substates.

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Language(s): eng - English
 Dates: 2014-08-122014-09-22
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1002/anie.201403102
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Title: Angewandte Chemie International Edition
Source Genre: Journal
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Pages: - Volume / Issue: 53 (39) Sequence Number: - Start / End Page: 10367 - 10371 Identifier: -