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Journal Article

A designed conformational shift to control protein binding specificity.

MPS-Authors
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Michielssens,  S.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Peters,  J. H.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Ban,  D.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Pratihar,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Seeliger,  D.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Sharma,  M.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Giller,  K.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Sabo,  T. M.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Becker,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Lee,  D.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Griesinger,  C.       
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

External Resource

http://onlinelibrary.wiley.com/doi/10.1002/anie.201403102/pdf
(Publisher version)

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Fulltext (public)

2069838.pdf
(Publisher version), 2MB

Supplementary Material (public)

2069838_Suppl.pdf
(Supplementary material), 2MB

Citation

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.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-282F-0
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.