7SK8

Cryo-EM structure of human ACKR3 in complex with CXCL12, a small molecule partial agonist CCX662, an extracellular Fab, and an intracellular Fab

Summary for 7SK8

• Entry DOI: 10.2210/pdb7sk8/pdb
• EMDB information: 25176
• Descriptor: Atypical chemokine receptor 3, Stromal cell-derived factor 1, CID25 Fab light chain, ... (9 entities in total)
• Functional Keywords: atypical chemokine receptor, membrane protein, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 154884.44

Authors

Yen, Y.C.,Schafer, C.T.,Gustavsson, M.,Handel, T.M.,Tesmer, J.J.G. (deposition date: 2021-10-19, release date: 2022-07-27, Last modification date: 2025-05-28)

Primary citation

Yen, Y.C.,Schafer, C.T.,Gustavsson, M.,Eberle, S.A.,Dominik, P.K.,Deneka, D.,Zhang, P.,Schall, T.J.,Kossiakoff, A.A.,Tesmer, J.J.G.,Handel, T.M.
Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias.
Sci Adv, 8:eabn8063-eabn8063, 2022

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 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.

PubMed: 35857509
DOI: 10.1126/sciadv.abn8063

Experimental method

ELECTRON MICROSCOPY (3.3 Å)