Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist

Isaikina, Polina and Tsai, Ching-Ju and Dietz, Nikolaus and Pamula, Filip and Grahl, Anne and Goldie, Kenneth N. and Guixà-González, Ramon and Branco, Camila and Paolini-Bertrand, Marianne and Calo, Nicolas and Cerini, Fabrice and Schertler, Gebhard F. X. and Hartley, Oliver and Stahlberg, Henning and Maier, Timm and Deupi, Xavier and Grzesiek, Stephan. (2021) Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist. Science Advances, 7 (25). eabg8685.

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The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric G; i; protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan and Isaikina, Polina and Dietz, Nikolaus and Maier, Timm and Goldie, Kenneth N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2023 04:10
Deposited On:27 Aug 2021 13:40

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