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

Pim J. de Vink, Sebastian A. Andrei, Yusuke Higuchi, Christian Ottmann, Lech-Gustav Milroy, Luc Brunsveld (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

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 EC 50 . 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, K D II , 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 K D II 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.

LanguageEnglish
Pages2869-2874
Number of pages6
JournalChemical Science
Volume10
Issue number10
DOIs
StatePublished - 2019

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Stabilization
Molecules
Proteins
14-3-3 Proteins
Fluorescence
Thermodynamics
Polarization

Cite this

de Vink, Pim J. ; Andrei, Sebastian A. ; Higuchi, Yusuke ; Ottmann, Christian ; Milroy, Lech-Gustav ; Brunsveld, Luc. / Cooperativity basis for small-molecule stabilization of protein-protein interactions. In: Chemical Science. 2019 ; Vol. 10, No. 10. pp. 2869-2874
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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 EC 50 . 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, K D II , 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 K D II 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.",
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Cooperativity basis for small-molecule stabilization of protein-protein interactions. / de Vink, Pim J.; Andrei, Sebastian A.; Higuchi, Yusuke; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, Luc (Corresponding author).

In: Chemical Science, Vol. 10, No. 10, 2019, p. 2869-2874.

Research output: Contribution to journalArticleAcademicpeer-review

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