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Title: Structural basis of ligand interaction with atypical chemokine receptor 3

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 β-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 ACKR3:CXCL12 and ACKR3:small-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 receptor:chemokine and receptor:small-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.

Authors:
; ; ; ; ; ; ORCiD logo; ; ; ORCiD logo;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409609
Report Number(s):
BNL-114661-2017-JA¿¿¿
Journal ID: ISSN 2041-1723
DOE Contract Number:  
SC0012704
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Gustavsson, Martin, Wang, Liwen, van Gils, Noortje, Stephens, Bryan S., Zhang, Penglie, Schall, Thomas J., Yang, Sichun, Abagyan, Ruben, Chance, Mark R., Kufareva, Irina, and Handel, Tracy M. Structural basis of ligand interaction with atypical chemokine receptor 3. United States: N. p., 2017. Web. doi:10.1038/ncomms14135.
Gustavsson, Martin, Wang, Liwen, van Gils, Noortje, Stephens, Bryan S., Zhang, Penglie, Schall, Thomas J., Yang, Sichun, Abagyan, Ruben, Chance, Mark R., Kufareva, Irina, & Handel, Tracy M. Structural basis of ligand interaction with atypical chemokine receptor 3. United States. doi:10.1038/ncomms14135.
Gustavsson, Martin, Wang, Liwen, van Gils, Noortje, Stephens, Bryan S., Zhang, Penglie, Schall, Thomas J., Yang, Sichun, Abagyan, Ruben, Chance, Mark R., Kufareva, Irina, and Handel, Tracy M. Wed . "Structural basis of ligand interaction with atypical chemokine receptor 3". United States. doi:10.1038/ncomms14135.
@article{osti_1409609,
title = {Structural basis of ligand interaction with atypical chemokine receptor 3},
author = {Gustavsson, Martin and Wang, Liwen and van Gils, Noortje and Stephens, Bryan S. and Zhang, Penglie and Schall, Thomas J. and Yang, Sichun and Abagyan, Ruben and Chance, Mark R. and Kufareva, Irina and Handel, Tracy M.},
abstractNote = {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 β-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 ACKR3:CXCL12 and ACKR3:small-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 receptor:chemokine and receptor:small-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.},
doi = {10.1038/ncomms14135},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = {Wed Jan 18 00:00:00 EST 2017},
month = {Wed Jan 18 00:00:00 EST 2017}
}