Ligand-Based NMR Study of C‑X‑C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells

Peptide-binding
G protein-coupled receptors (GPCRs) are key effectors
in numerous pathological and physiological pathways. The assessment
of the receptor-bound conformation of a peptidic ligand within a membrane
receptor such as a GPCR is of great impact for a rational drug design
of more potent analogues. In this work, we applied multiple ligand-based
nuclear magnetic resonance (NMR) methods to study the interaction
of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12),
and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human
T-Leukemia cells (CCRF-CEM cells). This study represents the first
structural investigation reporting the receptor-bound conformation
of a peptide to a GPCR directly on a living cell. The results obtained
in the field of CXCL12/CXCR4 are proofs of concept, although important
information for researchers dealing with the CXCR4 field arises. General
application of the presented NMR methodologies is possible and surely
may help to boost the development of new therapeutic agents targeting
GPCRs.