Structural insights into galanin receptor signaling

Jiang, Wenbin; Zheng, Sanduo

doi:10.1073/pnas.2121465119

Cited by 17 publications

(5 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7 ). Of note, galanin, located far away from the receptor core 60 , 61 , adopted an α-helical structure that sat flat on the top of the orthosteric pocket with formation of massive contacts with ECLs 1-3 and moderate interface area (~1600 Å 2 ). Different from the above peptide-binding modes, INSL5 penetrates into the orthosteric pocket via its B chain C terminus by adopting a single α-helix conformation, which is distinct from all reported peptide-bound class A GPCRs but closer to those seen with class B1 structures bound by peptides, such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon whose N termini insert deeply into the TMD core.…”

Section: Resultsmentioning

confidence: 99%

Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

et al. 2023

View full text Add to dashboard Cite

Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4–Gi protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single α-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily.

show abstract

Section: Resultsmentioning

confidence: 99%

Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Notably, most receptors including GPR174, GPR21, GPR52, CCK1R, and NK1R that adopt non-canonical G s coupling mode have been reported to promiscuously couple to other G protein subtypes 9 , 39 – 42 . Our previous studies have shown that a larger hydrophobic residue (L) at 5.65 is dominant in G q - and G i/o -coupled receptors 37 , 48 . Mutation of L214 5.65 in galanin receptor 2 to alanine almost abolished G q recruitment, indicating its critical role for G q coupling 48 .…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies have shown that a larger hydrophobic residue (L) at 5.65 is dominant in G q - and G i/o -coupled receptors 37 , 48 . Mutation of L214 5.65 in galanin receptor 2 to alanine almost abolished G q recruitment, indicating its critical role for G q coupling 48 . Despite differences in conformational changes of TM6 and the hook in Gα between canonical and non-canonical G s coupling mode, a common feature of GPCRs and G s coupling is the insertion of a large hydrophobic residue at the position 34.51 of ICL2 into a hydrophobic groove in the Ras domain of Gα (Fig.…”

Section: Resultsmentioning

confidence: 99%

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling

Nie,

Qiu,

Chen

et al. 2023

Nat Commun

Self Cite

View full text Add to dashboard Cite

Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒Gs, GPR161‒Gs and GPR174‒Gs complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent manner. Moreover, GPR174 adopts a non-canonical Gs coupling mode. The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands.

show abstract

“…7 ). Of note, galanin, located far away from the receptor core 55,56 , adopted an α-helical structure that sat flat on the top of the orthosteric pocket with formation of massive contacts with ECLs 1-3 and moderate interface area (∼1600 Å 2 ). Different from the above peptide-binding modes, INSL5 penetrates into the orthosteric pocket via its B chain C terminus by adopting a single α-helix conformation, which is distinct from all reported peptide-bound class A GPCRs but closer to those seen with class B1 structures bound by peptides, such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon whose N termini insert deeply into the TMD core.…”

Section: Resultsmentioning

confidence: 99%

A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)

Chen

Zhou

Wang

et al. 2022

Preprint

View full text Add to dashboard Cite

Members of the insulin superfamily regulate a variety of biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs), which are class A G protein-coupled receptors (GPCRs), to exert pleiotropic actions. Here, we report three cryo-electron microscopy structures of RXFP4—Gi protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053, both were discovered through medicinal chemistry efforts. The B chain of INSL5 adopts a single α-helix that penetrates into the orthostatic pocket, while the A chain sits above the orthosteric pocket to interact with the extracellular surface of RXFP4, revealing a unique peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. DC591053 selectively mimicked the action of INSL5 at RXFP4 whereas compound 4 activated both RXFP3 and RXFP4. Comparison of peptide binding modes within the insulin superfamily displayed diverse interaction mechanisms distinct to each type of the peptides. Our findings not only provide valuable insights into ligand recognition and subtype selectivity among class A GPCRs, but also expand the knowledge of signaling mechanisms in the insulin superfamily.

show abstract

Structural insights into galanin receptor signaling

Cited by 17 publications

References 74 publications

Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling

A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)

Contact Info

Product

Resources

About