Biased signaling of G protein-coupled receptors – From a chemokine receptor CCR7 perspective

Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both Gi/o and Gq/11. IP1 accumulation and Ca2+ flux arose from Gq/11 activation, rather than from Gβγ subunit release after Gi/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for Gq/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for Gi/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to Gq/11 rather than to Gi/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

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Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1

Nature Chemical Biology ◽

10.1038/s41589-021-00918-z ◽

2021 ◽

Author(s):

Zhehua Shao ◽

Qingya Shen ◽

Bingpeng Yao ◽

Chunyou Mao ◽

Li-Nan Chen ◽

...

Keyword(s):

G Protein ◽

Chemokine Receptor ◽

Binding Pocket ◽

Structural Basis ◽

Free Form ◽

Downstream Signaling ◽

Receptor Complexes ◽

Ligand Free ◽

Biased Signaling ◽

G Protein Coupled

AbstractBiased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1–Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6–2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine–receptor complexes, providing new insights into the mode of chemokine recognition.

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Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2020.165973 ◽

2021 ◽

Vol 1867 (1) ◽

pp. 165973 ◽

Cited By ~ 2

Author(s):

Li-Kun Yang ◽

Zhi-Shuai Hou ◽

Ya-Xiong Tao

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Human Diseases ◽

Naturally Occurring ◽

Biased Signaling ◽

G Protein Coupled

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Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

Science Advances ◽

10.1126/sciadv.abf5325 ◽

2021 ◽

Vol 7 (24) ◽

pp. eabf5325

Author(s):

Shintaro Maeda ◽

Yuki Shiimura ◽

Hidetsugu Asada ◽

Kunio Hirata ◽

Fangjia Luo ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Structural Basis ◽

Active Conformation ◽

Vascular Integrity ◽

Biased Signaling ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled ◽

Alkyl Tail ◽

Insight Into

Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.

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