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Issue 10, 2019
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Cooperativity basis for small-molecule stabilization of protein–protein interactions

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Abstract

A cooperativity framework to describe and interpret small-molecule stabilization of protein–protein interactions (PPI) is presented. The stabilization of PPIs is a versatile and emerging therapeutic strategy to target specific combinations of protein partners within the protein interactome. Currently, the potency of PPI stabilizers is typically expressed by their apparent affinity or EC50. Here, we propose that the effect of a PPI stabilizer be best described involving the cooperativity factor, α, between the stabilizer and binding partners in addition to the intrinsic affinity, KDII, of the stabilizer for one of the apo-proteins. By way of illustration, we combine fluorescence polarization measurements with thermodynamic modeling to determine the α and KDII for the PPI stabilization of 14-3-3 and TASK3 by fusicoccin-A (FC-A) and validate our approach by studying other PPI-partners of 14-3-3 proteins. Finally, we characterize a library of different stabilizer compounds, and perform structure–activity relationship studies in which molecular changes could be attributed to either changes in cooperativity or intrinsic affinity. Such insights should aid in the development of more effective protein–protein stabilizer drugs.

Graphical abstract: Cooperativity basis for small-molecule stabilization of protein–protein interactions

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Publication details

The article was received on 25 Nov 2018, accepted on 25 Jan 2019 and first published on 25 Jan 2019


Article type: Edge Article
DOI: 10.1039/C8SC05242E
Chem. Sci., 2019,10, 2869-2874
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Cooperativity basis for small-molecule stabilization of protein–protein interactions

    P. J. de Vink, S. A. Andrei, Y. Higuchi, C. Ottmann, L. Milroy and L. Brunsveld, Chem. Sci., 2019, 10, 2869
    DOI: 10.1039/C8SC05242E

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