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-Structure paper
Title | Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. |
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Journal, issue, pages | Sci Adv, Vol. 8, Issue 28, Page eabn8063, Year 2022 |
Publish date | Jul 15, 2022 |
Authors | Yu-Chen Yen / Christopher T Schafer / Martin Gustavsson / Stefanie A Eberle / Pawel K Dominik / Dawid Deneka / Penglie Zhang / Thomas J Schall / Anthony A Kossiakoff / John J G Tesmer / Tracy M Handel / |
PubMed Abstract | 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 ...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. |
External links | Sci Adv / PubMed:35857509 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.3 - 4.0 Å |
Structure data | EMDB-25171, PDB-7sk3: EMDB-25172, PDB-7sk4: EMDB-25173, PDB-7sk5: EMDB-25174, PDB-7sk6: EMDB-25175, PDB-7sk7: EMDB-25176, PDB-7sk8: EMDB-25177, PDB-7sk9: |
Chemicals | ChemComp-CLR: ChemComp-GJ9: ChemComp-LMN: |
Source |
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Keywords | SIGNALING PROTEIN/IMMUNE SYSTEM / Atypical Chemokine Receptor / MEMBRANE PROTEIN / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex |