Conformational dynamics underlying atypical chemokine receptor 3 activation

• 成果类型: Article
• 署名作者: Otun, Omolade; Aljamous, Christelle; Del Nero, Elise; Arimont-Segura, Marta; Bosma, Reggie; Zarzycka, Barbara; Girbau, Tristan; Leyrat, Cedric; de Graaf, Chris; Leurs, Rob; Durroux, Thierry; Granier, Sebastien; Cong, Xiaojing; Bechara, Cherine
• 署名单位: Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier; Vrije Universiteit Amsterdam; Institut Universitaire de France; Heptares Therapeutics Ltd.
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11139
• DOI: 10.1073/pnas.2404000121
• 发表日期: 2024-07-23
• 关键词: replica exchange; beta-arrestin; protein; simulations; mechanism; reveals; agonist; cxcr4; rdc1

摘要

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 beta- arrestin 1 binding. In summary, this study highlights the structure- function relationship of small ligands, the binding mode of beta- arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.