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

Abstract

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 the pathology of cancer, HIV, and COVID-19. Despite its significance as a drug target, the 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 Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N-terminus of agonist chemokines pushes onto an aromatic connector that transmits activation to the canonical GPCR microswitch network. This activation mechanism differs significantly from other CC chemokine receptors that bind shorter chemokines in a shallow binding mode and have unique sequence signatures and a specialized activation mechanism.One-sentence summaryThe structure of CCR5 in complex with the chemokine agonist [6P4]CCL5 and the heterotrimeric Gi protein reveals its activation mechanism

Evolving cryo-EM structural approaches for GPCR drug discovery

“…Excitingly, while the global resolution was 0.2-0.4 Å lower, the structure determined from the Glacios-Falcon 4 data was effectively identical for the small-molecule binding pocket, including the water network within this pocket. While direct comparator data with 300 kV imaging is not available, a recent publication in bioRxiv reports a CCR5-agonist-G protein complex resolved to 3.1 Å resolution using a Glacios-K3 system (Isaikina et al, 2020), further supporting the potential utility of 200 kV cryo-EM for GPCR structure determination.…”

Evolving cryo-EM structural approaches for GPCR drug discovery

“…Excitingly, while the global resolution was 0.2-0.4 Å lower, the structure determined from the Glacios-Falcon 4 data was effectively identical for the small molecule binding pocket, including the water network within this pocket. While direct comparator data with 300kV imaging is not available, a recent publication in BioRxiv reports a CCR5-agonist-G protein complex resolved to 3.1 Å resolution using a Glacios-K3 system 37 , further supporting the potential utility of 200kV cryo-EM for GPCR structure determination.…”