Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2

Toy L, Huber M, Schmidt M, Weikert D, Schiedel M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

DOI: 10.1021/acschembio.2c00263

Abstract

Fluorescently labeled ligands are versatile molecular tools to study G protein-coupled receptors (GPCRs) and can be used for a range of different applications, including bio-luminescence resonance energy transfer (BRET) assays. Here, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a drug target in oncology and inflammation. Starting from previously reported intracellular CCR2 antagonists, several tetramethylrhodamine (TAMRA)-labeled CCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CCR2. By means of these studies, we developed 14 as a fluorescent CCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a non-isotopic and high-throughput manner. Further, we show that 14 can be used as a tool for fragment-based screening approaches. Thus, our small-molecule-based fluorescent CCR2 ligand 14 represents a promising tool for future studies of CCR2 pharmacology.

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How to cite

APA:

Toy, L., Huber, M., Schmidt, M., Weikert, D., & Schiedel, M. (2022). Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2. ACS Chemical Biology. https://dx.doi.org/10.1021/acschembio.2c00263

MLA:

Toy, Lara, et al. "Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR2." ACS Chemical Biology (2022).

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