Probing Functional Heteromeric Chemokine Protein-Protein Interactions through Conformation-Assisted Oxime Ligation

Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially invo...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2016-11, Vol.55 (48), p.14963-14966
Main Authors: Agten, Stijn M., Koenen, Rory R., Ippel, Hans, Eckardt, Veit, von Hundelshausen, Philipp, Mayo, Kevin H., Weber, Christian, Hackeng, Tilman M.
Format: Article
Language:English
Subjects:
atherosclerosis
Chemokines
Chemokines - chemistry
Communication
Communications
Endothelial Cells - chemistry
Humans
Models, Molecular
Molecular Conformation
oximes
Oximes - chemistry
Protein Binding
protein-protein interactions
Proteins
solid-phase synthesis
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Summary:Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES‐PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function. Kissing chemokines: Heteromeric chemokine interactions are implicated in various inflammatory diseases. Because it is unclear whether pathological effects are caused by heterodimerization or by additive effects of separate chemokines, a covalent oxime‐linked chemokine heterodimer was synthesized. Oxime ligation was accelerated by interactions between the chemokines, and the heterodimer showed enhanced function compared to mixed chemokines.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201607036