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TitleStructural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist.
Journal, issue, pagesSci Adv, Vol. 7, Issue 25, Year 2021
Publish dateJun 16, 2021
AuthorsPolina Isaikina / Ching-Ju Tsai / Nikolaus Dietz / Filip Pamula / Anne Grahl / Kenneth N Goldie / Ramon Guixà-González / Camila Branco / Marianne Paolini-Bertrand / Nicolas Calo / Fabrice Cerini / Gebhard F X Schertler / Oliver Hartley / Henning Stahlberg / Timm Maier / Xavier Deupi / Stephan Grzesiek /
PubMed AbstractThe 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 ...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 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.
External linksSci Adv / PubMed:34134983 / PubMed Central
MethodsEM (single particle)
Resolution3.15 Å
Structure data

12746

7o7f

EMDB-12746, PDB-7o7f:
Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist
Method: EM (single particle) / Resolution: 3.15 Å

Source
  • homo sapiens (human)
  • bos taurus (cattle)
  • mus musculus (house mouse)
  • Bovine (cattle)
KeywordsSIGNALING PROTEIN / G protein-coupled receptor (GPCR); CCR5; CCL5/RANTES; HIV entry; AIDS; membrane protein structure; / MEMBRANE PROTEIN

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