| Structural highlights
Function
CCL1_HUMAN Cytokine that is chemotactic for monocytes but not for neutrophils. Binds to CCR8.[1] CCR8_HUMAN Receptor for the chemokine CCL1/SCYA1/I-309. May regulate monocyte chemotaxis and thymic cell line apoptosis. Alternative coreceptor with CD4 for HIV-1 infection.[2] [3] [4] [5]
Publication Abstract from PubMed
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.
Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8.,Sun D, Sun Y, Janezic E, Zhou T, Johnson M, Azumaya C, Noreng S, Chiu C, Seki A, Arenzana TL, Nicoludis JM, Shi Y, Wang B, Ho H, Joshi P, Tam C, Payandeh J, Comps-Agrar L, Wang J, Rutz S, Koerber JT, Masureel M Nat Commun. 2023 Dec 1;14(1):7940. doi: 10.1038/s41467-023-43601-8. PMID:38040762[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Miller MD, Krangel MS. The human cytokine I-309 is a monocyte chemoattractant. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2950-4. PMID:1557400
- ↑ Garlisi CG, Xiao H, Tian F, Hedrick JA, Billah MM, Egan RW, Umland SP. The assignment of chemokine-chemokine receptor pairs: TARC and MIP-1 beta are not ligands for human CC-chemokine receptor 8. Eur J Immunol. 1999 Oct;29(10):3210-5. PMID:10540332 doi:http://dx.doi.org/10.1002/(SICI)1521-4141(199910)29:10<3210::AID-IMMU3210>3.0.CO;2-W
- ↑ Tiffany HL, Lautens LL, Gao JL, Pease J, Locati M, Combadiere C, Modi W, Bonner TI, Murphy PM. Identification of CCR8: a human monocyte and thymus receptor for the CC chemokine I-309. J Exp Med. 1997 Jul 7;186(1):165-70. PMID:9207005 doi:10.1084/jem.186.1.165
- ↑ Goya I, Gutiérrez J, Varona R, Kremer L, Zaballos A, Márquez G. Identification of CCR8 as the specific receptor for the human beta-chemokine I-309: cloning and molecular characterization of murine CCR8 as the receptor for TCA-3. J Immunol. 1998 Feb 15;160(4):1975-81 PMID:9469461
- ↑ Bernardini G, Hedrick J, Sozzani S, Luini W, Spinetti G, Weiss M, Menon S, Zlotnik A, Mantovani A, Santoni A, Napolitano M. Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor. Eur J Immunol. 1998 Feb;28(2):582-8. PMID:9521068 doi:<582::AID-IMMU582>3.0.CO;2-A 10.1002/(SICI)1521-4141(199802)28:02<582::AID-IMMU582>3.0.CO;2-A
- ↑ Sun D, Sun Y, Janezic E, Zhou T, Johnson M, Azumaya C, Noreng S, Chiu C, Seki A, Arenzana TL, Nicoludis JM, Shi Y, Wang B, Ho H, Joshi P, Tam C, Payandeh J, Comps-Agrar L, Wang J, Rutz S, Koerber JT, Masureel M. Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8. Nat Commun. 2023 Dec 1;14(1):7940. PMID:38040762 doi:10.1038/s41467-023-43601-8
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