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Cryo‐EM Structure of Atypical Chemokine Receptor 3 (ACKR3) in Complex with its Endogenous Ligand CXCL12
Author(s) -
Yen YuChen,
Schafer Christopher,
Gustavsson Martin,
Dominik Pawel,
Kossiakoff Martin,
Handel Tracy,
Tesmer John
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03785
Subject(s) - g protein coupled receptor , c c chemokine receptor type 6 , chemokine receptor , heterotrimeric g protein , microbiology and biotechnology , receptor , c c chemokine receptor type 7 , chemistry , xcl2 , arrestin , ligand (biochemistry) , ccl21 , chemokine , ccr1 , biology , g protein , biochemistry
CXCR7 is a seven‐transmembrane chemokine receptor that is involved in different stages of cancer progression. Unlike canonical G‐protein coupled receptors (GPCRs), CXCR7 has not been reported to activate signaling pathways through heterotrimeric G‐proteins when it binds to its endogenous ligand, CXCL12. Thus, one of the proposed molecular mechanisms for CXCR7 in cancer progression is through arrestin‐mediated signaling and/or by active sequestration of chemokine ligands. We determined by cryo‐electron microscopy (cryo‐EM) the 3.3 Å structure of CXCR7 in complex with a higher affinity variant of CXCL12 as well as extracellularly and intracellularly directed Fabs (CID25 and CID24, respectively) used as fiducials to aid the determination. CXCL12 binds to ACKR3 in a unique way from other chemokine complexes reported to date. CID25 stabilizes the extracellular loop 2 (ECL2) of the receptor and the 30s loop of chemokine, whereas the complementarity determining region 3 (CDR3) of CID24 inserts into the cytoplasmic pocket of the receptor, which overall adopts a conformation consistent with those of other GPCRs in an active configuration. The biochemical data demonstrates that CID25 does not affect β‐arrestin recruitment, indicating that the conformation of CID25‐bound receptor is physiologically relevant. The CXCR7‐CXCL12 structure reveals the interactions formed by the N‐terminus of CXCL12 in the orthosteric binding pocket of CXCR7 and how the N‐terminus of the receptor contributes to the core β‐sheet of CXCL12. The structure model may also guide the drug discovery targeting CXCR7 in the future and help explain its perceived bias towards GRK/arrestin signaling.