Biased agonists at the human Y1 receptor lead to prolonged membrane residency and extended receptor G protein interaction

Kaiser, Anette; Wanka, Lizzy; Ziffert, Isabelle; Beck‐Sickinger, Annette G.

doi:10.1007/s00018-019-03432-7

Cited by 7 publications

(6 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, the exchange of Q34 in NPY by proline relieves the steric issue in the Y 1 R binding pocket and mimics the positioning of PP at Y 4 R, resulting in unchanged binding affinity ( 5 , 12 ). The Q34G variant of NPY is also tolerated at Y 1 R but lacks the hydrophobic bulk packing against helices II and VII and may also enhance the local flexibility, explaining the 15-fold loss of binding affinity compared to NPY at Y 1 R ( 12 ). The position 34 is also critical for the natural selectivity of Y 2 R against PP.…”

Section: Resultsmentioning

confidence: 99%

Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors

et al. 2022

Self Cite

View full text Add to dashboard Cite

In response to three highly conserved neuropeptides, neuropeptide Y (NPY), peptide YY, and pancreatic polypeptide (PP), four G protein–coupled receptors mediate multiple essential physiological processes, such as food intake, vasoconstriction, sedation, and memory retention. Here, we report the structures of the human Y 1 , Y 2 , and Y 4 receptors in complex with NPY or PP, and the G i1 protein. These structures reveal distinct binding poses of the peptide upon coupling to different receptors, reflecting the importance of the conformational plasticity of the peptide in recognizing the NPY receptors. The N terminus of the peptide forms extensive interactions with the Y 1 receptor, but not with the Y 2 and Y 4 receptors. Supported by mutagenesis and functional studies, subtype-specific interactions between the receptors and peptides were further observed. These findings provide insight into key factors that govern NPY signal recognition and transduction, and would enable development of selective drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our work has broader implications for other neuropeptide GPCRs. Pharmacological studies with other neuropeptides, including opioid peptides 36 , neuropeptide S 37 , and neuropeptide Y 38 suggest that interactions between the divergent, less conserved regions of the neuropeptide and their cognate receptor extracellular loops, which also diverge in sequence, can tune signaling efficacy via multiple G proteins or β-arrestins. Our work highlights the role of peptide-receptor extracellular contacts in determining the conformational flexibility of the core “message” region of SP.…”

Section: Discussionmentioning

confidence: 99%

Selective G protein signaling driven by substance P–neurokinin receptor dynamics

et al. 2021

View full text Add to dashboard Cite

The neuropeptide Substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G q and G s proteins. Neurokinin A also activates NK1R, but leads to selective G q signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryo-EM structures of active NK1R bound to SP or the G q -biased peptide SP6–11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G s signaling but not G q signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6–11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.

show abstract

“…linearization abolished G protein-mediated responses and subsequent arr3 recruitment at the ET A R, but retained ET-1-like signaling at the ET B R. However, compared to ET-1, peptide 1 displayed a reduced maximum recruitment of arr3, indicating a minor signaling bias for this agonist in comparison to the wt ligand, which we report for the first time. Biased agonism has been discovered for other peptide-binding GPCRs like the angiotensin II receptor type 1 and the members of the neuropeptide Y receptor family [35][36][37]. Monocyclic peptide 2 exhibited ET-1-like G protein signaling, arr3 recruitment and cellular internalization of both ET A R and ET B R. Peptides with increased ring sizes (peptides 3-5) behaved similar to the ET B R-selective peptide 1 concerning the fast recruitment kinetics of arr3 to activated ET B R and recruitment potency and efficacy.…”

mentioning

confidence: 99%

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Wolf

Beck‐Sickinger

2021

Journal of Peptide Science

Self Cite

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) like hypertension are a major cause for death worldwide. In the cardiovascular tissue, the endothelin system—consisting of the receptor subtypes A (ETAR) and B (ETBR) and the mixed agonist endothelin 1 (ET‐1)—is a major key player in the regulation of vascular tone and blood pressure. Tight control of this system is required to maintain homeostasis; otherwise, the endothelin system can cause severe CVDs like pulmonary artery hypertension. The high sequence homology between both receptor subtypes limits the development of novel and selective ligands. Identification of small differences in receptor–ligand interactions and determination of selectivity constraints are crucial to fine‐tune ligand properties and subsequent signaling events. Here, we report on novel ET‐1 analogs and their detailed pharmacological characterization. We generated simplified ET‐1‐derived monocyclic peptides to provide an accessible synthesis route. By detailed in vitro characterization, we demonstrated that both G protein signaling and the subsequent arrestin recruitment of activated ETBR remain intact, whereas activation of the ETAR depends on the intramolecular ring size. Increasing of the intramolecular ring structure reduces activity at the ETAR and shifts the peptide toward ETBR selectivity. All ET‐1 analogs displayed efficient ETBR‐mediated signaling by G protein activation and arrestin 3 recruitment. Our study provides in‐depth characterization of the ET‐1/ETAR and ET‐1/ETBR interactions, which has the potential for future development of endothelin‐based drugs for CVD treatment. By identification of Lys9 for selective labeling, novel analogs for peptide‐mediated shuttling by ET‐1 are proposed.

show abstract

Biased agonists at the human Y1 receptor lead to prolonged membrane residency and extended receptor G protein interaction

Cited by 7 publications

References 53 publications

Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors

Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors

Selective G protein signaling driven by substance P–neurokinin receptor dynamics

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Contact Info

Product

Resources

About