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