Conformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR1

The dynamic interactions between G protein-coupled receptors (GPCRs) and their cognate protein partners are central to several cell signaling pathways. For example, the association of CXC chemokine receptor 1 (CXCR1) with its chemokine, interleukin-8 (IL8 or CXCL8) initiates pathways leading neutrophil-mediated immune responses. N-terminal domain confers ligand selectivity, but unfortunately conformational dynamics this intrinsically disordered region remains unresolved. In work, we have explored interaction CXCR1 IL8 by microsecond time scale coarse-grain simulations, complemented atomistic models NMR chemical shift predictions. We show that plasticity apo -receptor is restricted upon binding, driving it an open C-shaped conformation. Importantly, corroborated complex sampled in our simulations against perturbations reported previous studies trends similar. Our results indicate perturbation often not a reporter residue contacts such associations. believe represent step forward devising strategy understand regions GPCRs how they acquire functionally important ensembles protein-protein interfaces.