Advanced fluorescence microscopy reveals disruption of dynamic CXCR4 dimerization by subpocket-specific inverse agonists

• DOI: 10.1073/pnas.2013319117
• Publication Date: 2020-11-05T00:51:07Z
• Authors: Ali Işbilir; Jan Möller; Marta Arimont; Vladimir Bobkov; Cristina Perpiñá-...; Carsten Hoffmann; Asuka Inoue; Raimond Heukers; Chris de Graaf; Martine J. Smit; Paolo Annibale; Martin J. Lohse
• Keywords: Single-molecule experiment

Significance Class A G protein−coupled receptors (GPCRs) can form dimers and oligomers via poorly understood mechanisms. We show here that the chemokine receptor CXCR4, which is a major pharmacological target, has an oligomerization behavior modulated by its active conformation. Combining advanced, single-molecule, single-cell optical tools with functional assays computational approaches, we unveil three key features of CXCR4 quaternary organization: dimerization 1) dynamic, 2) increases expression level, 3) be disrupted stabilizing inactive Ligand binding motifs reveal ligand subpocket essential to modulate both basal activity dimerization. This relevant develop new strategies design CXCR4-targeting drugs.