Conformational dynamics underlying atypical chemokine receptor 3 activation

Omolade Otun; Christelle Aljamous; Elise Del Nero; Marta Arimont-Segura; Reggie Bosma; Barbara Zarzycka; Tristan Girbau; Cédric Leyrat; Chris de Graaf; Rob Leurs; Thierry Durroux; Sébastien Granier; Xiaojing Cong; Cherine Bechara

doi:10.1073/pnas.2404000121

Conformational dynamics underlying atypical chemokine receptor 3 activation

Omolade Otun, Christelle Aljamous, Elise Del Nero, Marta Arimont-Segura, Reggie Bosma, Barbara Zarzycka, Tristan Girbau, Cédric Leyrat, Chris de Graaf, Rob Leurs, Thierry Durroux, Sébastien Granier, Xiaojing Cong, Cherine Bechara

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

Abstract

Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.

Original language	English
Article number	e2404000121
Pages (from-to)	1-12
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	30
Early online date	15 Jul 2024
DOIs	https://doi.org/10.1073/pnas.2404000121
Publication status	Published - 23 Jul 2024

Funding

This research was funded by European Union (H2020-MSCA Program, Grant agreement 860229-ONCORNET2.0 and Grant Agreement 641833-ONCORNET). Technical assistance of Drs. Simon Mobach is highly valued. Mass spectrometry experiments were carried out using the facilities of the P\u00F4le Prot\u00E9ome de Montpellier (BioCampus Montpellier). This work was supported by the European Regional Development Fund/R\u00E9gion Occitanie, Montpellier Universit\u00E9 d\u2019Excellence, Labex EpiGenMed, and the French Agence Nationale de la Recherche (projects LEUKOCEPTOR ANR-21-CE44-0007-01 and OCHRE no R19168LL). MD simulations were performed using HPC resources from GENCI-TGCC France. ACKNOWLEDGMENTS. This research was funded by European Union (H2020-MSCA Program, Grant agreement 860229-ONCORNET2.0 and Grant Agreement 641833-ONCORNET).Technical assistanceof Drs.SimonMobach ishighlyvalued. Mass spectrometry experiments were carried out using the facilities of the P\u00F4le Prot\u00E9ome de Montpellier (BioCampus Montpellier). This work was supported by the European Regional Development Fund/R\u00E9gion Occitanie, Montpellier Universit\u00E9 d\u2019Excellence, Labex EpiGenMed, and the French Agence Nationale de la Recherche (projects LEUKOCEPTOR ANR-21-CE44-0007-01 and OCHRE no R19168LL). MD simulations were performed using HPC resources from GENCI-TGCC France.

Funders	Funder number
Pôle Protéome de Montpellier
Horizon 2020 Framework Programme
European Commission
GENCI-TGCC
Région
European Regional Development Fund
Agence Nationale de la Recherche	ANR-21-CE44-0007-01, R19168LL, ANR-21-CE44-0007
H2020 Marie Skłodowska-Curie Actions	860229-ONCORNET2.0, 641833

Keywords

ACKR3
GPCR conformational dynamics
HDX-MS
MD simulations

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10.1073/pnas.2404000121

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Otun, O., Aljamous, C., Del Nero, E., Arimont-Segura, M., Bosma, R., Zarzycka, B., Girbau, T., Leyrat, C., de Graaf, C., Leurs, R., Durroux, T., Granier, S., Cong, X., & Bechara, C. (2024). Conformational dynamics underlying atypical chemokine receptor 3 activation. Proceedings of the National Academy of Sciences of the United States of America, 121(30), 1-12. Article e2404000121. https://doi.org/10.1073/pnas.2404000121

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title = "Conformational dynamics underlying atypical chemokine receptor 3 activation",

abstract = "Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.",

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author = "Omolade Otun and Christelle Aljamous and \{Del Nero\}, Elise and Marta Arimont-Segura and Reggie Bosma and Barbara Zarzycka and Tristan Girbau and C{\'e}dric Leyrat and \{de Graaf\}, Chris and Rob Leurs and Thierry Durroux and S{\'e}bastien Granier and Xiaojing Cong and Cherine Bechara",

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Otun, O, Aljamous, C, Del Nero, E, Arimont-Segura, M, Bosma, R, Zarzycka, B, Girbau, T, Leyrat, C, de Graaf, C, Leurs, R, Durroux, T, Granier, S, Cong, X & Bechara, C 2024, 'Conformational dynamics underlying atypical chemokine receptor 3 activation', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 30, e2404000121, pp. 1-12. https://doi.org/10.1073/pnas.2404000121

TY - JOUR

T1 - Conformational dynamics underlying atypical chemokine receptor 3 activation

AU - Otun, Omolade

AU - Aljamous, Christelle

AU - Del Nero, Elise

AU - Arimont-Segura, Marta

AU - Bosma, Reggie

AU - Zarzycka, Barbara

AU - Girbau, Tristan

AU - Leyrat, Cédric

AU - de Graaf, Chris

AU - Leurs, Rob

AU - Durroux, Thierry

AU - Granier, Sébastien

AU - Cong, Xiaojing

AU - Bechara, Cherine

PY - 2024/7/23

Y1 - 2024/7/23

N2 - Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.

AB - Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.

KW - ACKR3

KW - GPCR conformational dynamics

KW - HDX-MS

KW - MD simulations

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JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Conformational dynamics underlying atypical chemokine receptor 3 activation

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