Structural basis of ligand interaction with atypical chemokine receptor 3.
Nat Commun
; 8: 14135, 2017 01 18.
Article
em En
| MEDLINE
| ID: mdl-28098154
ABSTRACT
Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through ß-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3CXCL12 and ACKR3small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptorchemokine and receptorsmall-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores CXCR
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article