Published July 13, 2022
| Version v1
Journal article
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Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias
Creators
- 1. Purdue University
- 2. University of California, San Diego
- 3. University of Copenhagen
- 4. University of Chicago
- 5. ChemoCentryx Inc.
Description
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.
Data availability
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.Files
sciadv.abn8063.pdf
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.abn8063
- Other
- oai:uchicago.tind.io:10962
Funding
- 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
- Villum Fonden
- Walther Cancer Foundation
- National Institutes of Health
- CA023168
- Robertson Foundation