Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1–Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6–2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine–receptor complexes, providing new insights into the mode of chemokine recognition.
Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC chemokine receptor–G-protein complexes: CCR2 bound to its endogenous ligand CCL2, and CCR3 in the apo state. The structure of the CCL2–CCR2–G-protein complex reveals that CCL2 inserts deeply into the extracellular half of the transmembrane domain, and forms substantial interactions with the receptor through the most N-terminal glutamine. Extensive hydrophobic and polar interactions are present between both two chemokine receptors and the Gα-protein, contributing to the constitutive activity of these receptors. Notably, complemented with functional experiments, the interactions around intracellular loop 2 of the receptors are found to be conserved and play a more critical role in G-protein activation than those around intracellular loop 3. Together, our findings provide structural insights into chemokine recognition and receptor activation, shedding lights on drug design targeting chemokine receptors.
Compelling evidence suggests that inflammatory components contribute to cancer development. However, eosinophils, involved in several inflammatory diseases, were not fully explored in cancer metastasis. We show that airway inflammatory eosinophilia and colonic inflammation with eosinophil infiltration are both associated with increased metastasis in mice. Eosinophilia is responsible for increased bone metastasis in eosinophil-enriched Cd3δ-Il-5 transgenic (Il-5 Tg) mice. We also observe increased eosinophils in the malignant pleural effusion of cancer patients with pleural metastasis. Mechanistically, eosinophils promote tumor cell migration and metastasis formation through secreting C-C motif chemokine ligand 6 (CCL6). Genetic knockout of Ccl6 in Il-5 Tg mice remarkably attenuates bone metastasis. Moreover, inhibition of C-C chemokine receptor 1 (CCR1, the receptor of CCL6) in tumor cells reduces tumor cell migration and metastasis. Thus, our study identifies a CCL6-dependent prometastatic activity of eosinophils, which can be inhibited by targeting CCR1 and represent an approach to preventing metastatic disease.
20 BACKGROUND The COVID-19 epidemic, first emerged in Wuhan during December 2019, has 21 spread globally. While the mass population movement for Chinese New Year has significantly 22 influenced spreading the disease, little direct evidence exists about the relevance to epidemic and its 23 control of population movement from Wuhan, local emergency response, and medical resources in 24 China. fatality rate was 2.84%, much higher in Hubei than in other regions (3.27% vs 0.73%). The index of 29 population inflow from Hubei was positively correlated with total (Provincial r=0.9159, p<0.001; 30 City r=0.6311, p<0.001) and primary cases (Provincial r=0.8702, p<0.001; City r=0.6358, p<0.001). 31 The local health emergency measures (eg, city lockdown and traffic control) were associated with 32 reduced infections nationwide. Moreover, the number of public health employees per capita was 33 inversely correlated with total cases (r=-0.6295, p <0.001) and infection rates (r =-0.4912, p <0.01). 34 Similarly, cities with less medical resources had higher fatality (r =-0.4791, p<0.01) and lower cure 35 rates (r = 0.5286, p<0.01) among the confirmed cases. 36 CONCLUSIONS The spread of the COVID-19 in China in its early phase was attributed primarily 37 to population movement from Hubei, and effective governmental health emergency measures and 38 adequate medical resources played important roles in subsequent control of epidemic and improved 39 prognosis of affected individuals.40 41 .CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not peer-reviewed) The copyright holder for this preprint .
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