title: Probing Functional Heteromeric Chemokine Protein-Protein Interactions through Conformation-Assisted Oxime Ligation.
abstract: 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.
authors: Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Stijn M
authors: SM
authors: Agten
authors: Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Rory R
authors: RR
authors: Koenen
authors: Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Hans
authors: H
authors: Ippel
authors: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität (LMU) München, Pettenkoferstraße 8a und 9, 80336, München, Germany.
authors: Veit
authors: V
authors: Eckardt
authors: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität (LMU) München, Pettenkoferstraße 8a und 9, 80336, München, Germany.
authors: Philipp
authors: P
authors: von Hundelshausen
authors: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 7-142 MCB, 420 Washington Ave SE, Minneapolis, MN, 55455, USA.
authors: Kevin H
authors: KH
authors: Mayo
authors: Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.|Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität (LMU) München, Pettenkoferstraße 8a und 9, 80336, München, Germany.
authors: Christian
authors: C
authors: Weber
authors: Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Tilman M
authors: 0000-0003-0142-0843
authors: TM
authors: Hackeng
mesh_terms: D018925:Chemokines / Q000737:chemistry*; D042783:Endothelial Cells / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D018925:Chemokines; D010091:Oximes
keywords: atherosclerosis; chemokines; oximes; protein-protein interactions; solid-phase synthesis