8U1U

Structure of a class A GPCR/agonist complex

Summary for 8U1U

• Entry DOI: 10.2210/pdb8u1u/pdb
• EMDB information: 41829
• Descriptor: C-C motif chemokine 1,C-C chemokine receptor type 8,EGFP fusion protein, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, agonist, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 202143.62

Authors

Sun, D.,Johnson, M.,Masureel, M. (deposition date: 2023-09-02, release date: 2023-12-20, Last modification date: 2024-10-23)

Primary citation

Sun, D.,Sun, Y.,Janezic, E.,Zhou, T.,Johnson, M.,Azumaya, C.,Noreng, S.,Chiu, C.,Seki, A.,Arenzana, T.L.,Nicoludis, J.M.,Shi, Y.,Wang, B.,Ho, H.,Joshi, P.,Tam, C.,Payandeh, J.,Comps-Agrar, L.,Wang, J.,Rutz, S.,Koerber, J.T.,Masureel, M.
Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8.
Nat Commun, 14:7940-7940, 2023

PubMed Abstract: The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in cancer. Targeting CCR8 with an antibody has appeared to be an attractive therapeutic approach, but the molecular basis for chemokine-mediated activation and antibody-mediated inhibition of CCR8 are not fully elucidated. Here, we obtain an antagonist antibody against human CCR8 and determine structures of CCR8 in complex with either the antibody or the endogenous agonist ligand CCL1. Our studies reveal characteristic antibody features allowing recognition of the CCR8 extracellular loops and CCL1-CCR8 interaction modes that are distinct from other chemokine receptor - ligand pairs. Informed by these structural insights, we demonstrate that CCL1 follows a two-step, two-site binding sequence to CCR8 and that antibody-mediated inhibition of CCL1 signaling can occur by preventing the second binding event. Together, our results provide a detailed structural and mechanistic framework of CCR8 activation and inhibition that expands our molecular understanding of chemokine - receptor interactions and offers insight into the development of therapeutic antibodies targeting chemokine GPCRs.

PubMed: 38040762
DOI: 10.1038/s41467-023-43601-8

Experimental method

ELECTRON MICROSCOPY (3.1 Å)