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

Research output: Contribution to journal › Journal article › Research › peer-review

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Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. / Yen, Yu Chen; Schafer, Christopher T.; Gustavsson, Martin; Eberle, Stefanie A.; Dominik, Pawel K.; Deneka, Dawid; Zhang, Penglie; Schall, Thomas J.; Kossiakoff, Anthony A.; Tesmer, John J.G.; Handel, Tracy M.

In: Science Advances, Vol. 8, No. 28, eabn8063, 07.2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Yen, YC, Schafer, CT, Gustavsson, M, Eberle, SA, Dominik, PK, Deneka, D, Zhang, P, Schall, TJ, Kossiakoff, AA, Tesmer, JJG & Handel, TM 2022, 'Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias', Science Advances, vol. 8, no. 28, eabn8063. https://doi.org/10.1126/sciadv.abn8063

APA

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. (2022). Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. Science Advances, 8(28), [eabn8063]. https://doi.org/10.1126/sciadv.abn8063

Vancouver

Yen YC, Schafer CT, Gustavsson M, Eberle SA, Dominik PK, Deneka D et al. Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. Science Advances. 2022 Jul;8(28). eabn8063. https://doi.org/10.1126/sciadv.abn8063

Author

Yen, Yu Chen ; Schafer, Christopher T. ; Gustavsson, Martin ; Eberle, Stefanie A. ; Dominik, Pawel K. ; Deneka, Dawid ; Zhang, Penglie ; Schall, Thomas J. ; Kossiakoff, Anthony A. ; Tesmer, John J.G. ; Handel, Tracy M. / Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. In: Science Advances. 2022 ; Vol. 8, No. 28.

Bibtex

@article{723afc30002f4c678e4f2420eb5757e6,
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 = "Yen, {Yu Chen} 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.}",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors, some rights reserved",
year = "2022",
month = jul,
doi = "10.1126/sciadv.abn8063",
language = "English",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "28",

}

RIS

TY - JOUR

T1 - Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias

AU - Yen, Yu Chen

AU - Schafer, Christopher T.

AU - Gustavsson, Martin

AU - Eberle, Stefanie A.

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.

N1 - Publisher Copyright: © 2022 The Authors, some rights reserved

PY - 2022/7

Y1 - 2022/7

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85134653199&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abn8063

DO - 10.1126/sciadv.abn8063

M3 - Journal article

C2 - 35857509

AN - SCOPUS:85134653199

VL - 8

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 28

M1 - eabn8063

ER -

ID: 316417640