TY - JOUR
T1 - Structural basis of G protein-Coupled receptor CMKLR1 activation and signaling induced by a chemerin-derived agonist
AU - Zhang, Xuan
AU - Weiß, Tina
AU - Cheng, Mary Hongying
AU - Chen, Siqi
AU - Ambrosius, Carla Katharina
AU - Czerniak, Anne Sophie
AU - Li, Kunpeng
AU - Feng, Mingye
AU - Bahar, Ivet
AU - Beck-Sickinger, Annette G.
AU - Zhang, Cheng
N1 - Publisher Copyright:
© 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/12
Y1 - 2023/12
N2 - ACUhe:mPolekainseec-loiknefirrmectheapttaollrh1ea(dCiMngKleLvRel1s)a,raerlseoprkenseonwtendacosrcrehcetmly:erin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both proand anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist- induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.
AB - ACUhe:mPolekainseec-loiknefirrmectheapttaollrh1ea(dCiMngKleLvRel1s)a,raerlseoprkenseonwtendacosrcrehcetmly:erin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both proand anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist- induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.
UR - https://www.scopus.com/pages/publications/85179014775
U2 - 10.1371/journal.pbio.3002188
DO - 10.1371/journal.pbio.3002188
M3 - Article
C2 - 38055679
AN - SCOPUS:85179014775
SN - 1544-9173
VL - 21
JO - PLoS Biology
JF - PLoS Biology
IS - 12
M1 - e3002188
ER -