Both CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are activated by the chemokine CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein–coupled receptor (GPCR), whereas ACKR3 is intrinsically biased for arrestin. The molecular basis for this difference is not understood. Here, we describe cryo-EM structures of ACKR3 in complex with CXCL12, a more potent CXCL12 variant, and a small-molecule agonist. The bound chemokines adopt an unexpected pose relative to those established for CXCR4 and observed in other receptor-chemokine complexes. Along with functional studies, these structures provide insight into the ligand-binding promiscuity of ACKR3, why it fails to couple to G proteins, and its bias toward β-arrestin. The results lay the groundwork for understanding the physiological interplay of ACKR3 with other GPCRs.
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Title
Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias
Data availability statement
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The structures of the seven ACKR3 complexes and the associated data have been deposited into the Protein Data Bank under accession codes 7SK3, 7SK4, 7SK5, 7SK6, 7SK7, 7SK8, and 7SK9, and the Electron Microscopy Data Bank under accession codes EMDB-25171, 25172, 25173, 25174, 25175, 25176, and 25177, respectively. The plasmids and other reagents can be provided pending scientific review and a completed material transfer agreement. Requests for the plasmids and other reagents should be submitted to the corresponding authors T.M.H. and J.J.G.T.
Funding Information
National Institutes of Health, AI161880 National Institutes of Health, CA254402 National Institutes of Health, CA221289 National Institutes of Health, HL071818 National Institutes of Health, P30CA023168 National Institutes of Health, GM117372 National Institutes of Health, GM137505 Canadian Thoracic Society, F32 GM137505 Robertson Research International Limited Miyuki Giken, 00025326 Kanazawa University Kræftfonden, F32 GM137505 National Institutes of Health, AI161880 Villum Fonden National Institutes of Health, CA254402 Walther Cancer Foundation National Institutes of Health, CA254402 National Institutes of Health, CA221289 National Institutes of Health, CA023168 National Institutes of Health, HL071818 National Institutes of Health, P30CA023168 National Institutes of Health, GM117372 National Institutes of Health, CA254402 National Institutes of Health, CA221289 National Institutes of Health, CA023168 National Institutes of Health, HL071818 National Institutes of Health, P30CA023168 National Institutes of Health, GM117372 Robertson Foundation
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