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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eabn8063 |
| Tidsskrift | Science Advances |
| Vol/bind | 8 |
| Udgave nummer | 28 |
| Antal sider | 13 |
| ISSN | 2375-2548 |
| DOI | |
| Status | Udgivet - jul. 2022 |
Bibliografisk note
Funding Information:We thank T. Klose in the Purdue Cryo-EM Facility for technical assistance. We thank S. S. Kim for assistance with ND reconstitutions and Fab generation. Support from the Purdue Center for Cancer Research Shared Resource small grant and Phase I and II Pilot Awards is gratefully acknowledged, P30CA023168.This work was supported by NIH grants AI161880 (T.M.H.), CA254402 (J.J.G.T. and T.M.H.), CA221289 (J.J.G.T.), CA023168 (J.J.G.T.), HL071818 (J.J.G.T.), P30CA023168 (J.J.G.T.), GM117372 (A.A.K.), and F32 GM137505 (C.T.S.); Walther Cancer Foundation (J.J.G.T.); Robertson Foundation/Cancer Research Institute Irvington Postdoctoral Fellowship (M.G.); and VILLUM FONDEN research grant 00025326 (M.G.).
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