Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8

Dawei Sun, Yonglian Sun, Eric Janezic, Tricia Zhou, Matthew Johnson, Caleigh Azumaya, Sigrid Noreng, Cecilia Chiu, Akiko Seki, Teresita L. Arenzana, John M. Nicoludis, Yongchang Shi, Baomei Wang, Hoangdung Ho, Prajakta Joshi, Christine Tam, Jian Payandeh, Laëtitia Comps-Agrar, Jianyong Wang, Sascha Rutz (), James T. Koerber () and Matthieu Masureel ()
Additional contact information
Dawei Sun: Genentech Inc.
Yonglian Sun: Genentech Inc.
Eric Janezic: Genentech Inc.
Tricia Zhou: Genentech Inc.
Matthew Johnson: Genentech Inc.
Caleigh Azumaya: Genentech Inc.
Sigrid Noreng: Genentech Inc.
Cecilia Chiu: Genentech Inc.
Akiko Seki: Genentech Inc.
Teresita L. Arenzana: Genentech Inc.
John M. Nicoludis: Genentech Inc.
Yongchang Shi: Genentech Inc.
Baomei Wang: Genentech Inc.
Hoangdung Ho: Genentech Inc.
Prajakta Joshi: Genentech Inc.
Christine Tam: Genentech Inc.
Jian Payandeh: Genentech Inc.
Laëtitia Comps-Agrar: Genentech Inc.
Jianyong Wang: Genentech Inc.
Sascha Rutz: Genentech Inc.
James T. Koerber: Genentech Inc.
Matthieu Masureel: Genentech Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43601-8

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DOI: 10.1038/s41467-023-43601-8

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