Journal: Proc Natl Acad Sci U S A / Year: 2026 Title: Structural insights into biased signaling at chemokine receptor CCR7. Authors: Kotaro Tanaka / Kouki Nishikawa / Yuki Shiimura / Yoshinori Fujiyoshi / Naotaka Tsutsumi / Abstract: CC chemokine receptor 7 (CCR7), which orchestrates adaptive immunity, exhibits a phenomenon known as biased agonism. CCL19 induces robust G-protein signaling and β-arrestin recruitment, leading to ...CC chemokine receptor 7 (CCR7), which orchestrates adaptive immunity, exhibits a phenomenon known as biased agonism. CCL19 induces robust G-protein signaling and β-arrestin recruitment, leading to transient signaling. In contrast, CCL21 preferentially activates G-protein pathways with minimal arrestin engagement, resulting in sustained signaling and differential functional outcomes. Here, we present the cryo-EM structures of the human CCR7-G complex with either CCL19 or CCL21. The structures reveal that while both engage a conserved orthosteric pocket, they adopt markedly distinct binding poses. Notably, the compact 30s loop of CCL21 inserts deeply into the receptor's extracellular vestibule, whereas the corresponding loop of CCL19 rests atop extracellular loop 2. Molecular dynamics simulations further reveal that these distinct binding modes induce differential intracellular dynamics, linked to the rotameric state of Y83 at the intracellular end of transmembrane helix 1. We demonstrate that CCL19 stabilizes a flexible conformational ensemble with a highly dynamic helix 8, creating a lateral opening favorable for GPCR kinase engagement. Conversely, CCL21 restricts this flexibility, locking the receptor in a state that precludes kinase interaction while maintaining G-protein coupling. Corroborated by functional data, these findings provide key insights into the structural basis of biased agonism at CCR7 and establish a foundation for rational design of pathway-selective immunomodulators.
Name: C-C motif chemokine 21 / type: protein_or_peptide / ID: 1 Details: CCL21 with a C-terminal linker to an expression/purification tag and the 3C protease scar Number of copies: 1 / Enantiomer: LEVO
Macromolecule #2: C-C chemokine receptor type 7,Non structural polyprotein
Macromolecule
Name: C-C chemokine receptor type 7,Non structural polyprotein type: protein_or_peptide / ID: 2 Details: CCR7 with a C-terminal LgBit-His tag. CLR is a bound small molecule, not a part of the polypeptide.,CCR7 with a C-terminal LgBit-His tag. CLR is a bound small molecule, not a part of the polypeptide. Number of copies: 1 / Enantiomer: LEVO
UniProtKB: C-C chemokine receptor type 7, Non structural polyprotein
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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2...
Macromolecule
Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 3 Details: chimeric protein with molecule 5 Gg2-Galpha(i)1 single chain fusion assigned a different chain ID for residue numbering,chimeric protein with molecule 5 Gg2-Galpha(i)1 single chain fusion ...Details: chimeric protein with molecule 5 Gg2-Galpha(i)1 single chain fusion assigned a different chain ID for residue numbering,chimeric protein with molecule 5 Gg2-Galpha(i)1 single chain fusion assigned a different chain ID for residue numbering Number of copies: 2 / Enantiomer: LEVO EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1
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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule
Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 4 Details: Gb1 with a C-terminal HiBit tag. The 3C protease scar and a short linker at the N-terminus. Number of copies: 1 / Enantiomer: LEVO
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Movie
Controller
Open data
Basic information
Map data
Sample
Keywords
Function and homology information
Homo sapiens (human) / 
Mus musculus (house mouse)
Authors
Japan, 3 items 
Citation
Structure visualization
Downloads & links
emd_66875.png
http://ftp.pdbj.org/pub/emdb/structures/EMD-66875
Z (Sec.)
Y (Row.)
X (Col.)
Sample components
Trichoplusia ni (cabbage looper)
Processing
Electron microscopy
FIELD EMISSION GUN
