Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias

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

doi:10.1126/sciadv.abn8063

Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias

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

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	eabn8063
Pages (from-to)	1-13
Number of pages	13
Journal	Science advances
Volume	8
Issue number	28
Early online date	13 Jul 2022
DOIs	https://doi.org/10.1126/sciadv.abn8063
Publication status	Published - 15 Jul 2022
Externally published	Yes

Funding

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.).

Funders	Funder number
Purdue Center for Cancer Research
European Commission
Walther Cancer Foundation
Irvington Postdoctoral Fellowship
Robertson Foundation/Cancer Research Institute
National Institutes of Health	F32 GM137505, P30CA023168
National Institute of Allergy and Infectious Diseases	R01AI161880
National Heart, Lung, and Blood Institute	R01HL071818
Seventh Framework Programme	254402
Villum Fonden	00025326
National Institute of General Medical Sciences	R01GM117372
National Cancer Institute	R01CA221289, R01CA254402

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title = "Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias",

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.",

author = "Yu-Chen Yen and Schafer, \{Christopher T.\} and Martin Gustavsson and Eberle, \{Stefanie A.\} and Dominik, \{Pawel K.\} and Dawid Deneka and Penglie Zhang and Schall, \{Thomas J.\} and Kossiakoff, \{Anthony A.\} and Tesmer, \{John J. G.\} and Handel, \{Tracy M.\}",

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AU - Dominik, Pawel K.

AU - Deneka, Dawid

AU - Zhang, Penglie

AU - Schall, Thomas J.

AU - Kossiakoff, Anthony A.

AU - Tesmer, John J. G.

AU - Handel, Tracy M.

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AB - 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.

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Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias

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