7vla
From Proteopedia
Cryo-EM structure of the CCL15(27-92) bound CCR1-Gi complex
Structural highlights
DiseaseCCR1_HUMAN Behcet disease. FunctionCCR1_HUMAN Chemokine receptor that plays a crucial role in regulating immune cell migration, inflammation, and immune responses (PubMed:14991608). Contributes to the inflammatory response by recruiting immune cells, such as monocytes, macrophages, T-cells, and dendritic cells, to sites of inflammation for the clearance of pathogens and the resolution of tissue damage. When activated by its ligands including CCL3, CCL5-9, CCL13-16 and CCL23, triggers a signaling cascade within immune cells, leading to their migration towards the source of the chemokine (PubMed:15905581). For example, mediates neutrophil migration after activation by CCL3 leading to the sequential release of TNF-alpha and leukotriene B4 (By similarity). Mediates also monocyte migration upon CXCL4 binding (PubMed:29930254). Activation by CCL5 results in neuroinflammation through the ERK1/2 signaling pathway (By similarity).[UniProtKB:P51675][1] [2] [3] Publication Abstract from PubMedBiased 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-G(i) complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 A, 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 (Y291(7.43)) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of beta-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. Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.,Shao Z, Shen Q, Yao B, Mao C, Chen LN, Zhang H, Shen DD, Zhang C, Li W, Du X, Li F, Ma H, Chen ZH, Xu HE, Ying S, Zhang Y, Shen H Nat Chem Biol. 2022 Mar;18(3):264-271. doi: 10.1038/s41589-021-00918-z. Epub 2021 , Dec 23. PMID:34949837[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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