Molecular basis for kinin selectivity and activation of the human bradykinin receptors

Yin, Yuanyuan; Ye, Chenyu; Zhou, Fulai; Wang, Jia; Yang, Dehua; Yin, Wanchao; Wang, Mingwei; Xu, H. Eric; Jiang, Yi

doi:10.1038/s41594-021-00645-y

Cited by 39 publications

(42 citation statements)

References 48 publications

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“…1). The Gα q chimera was generated based on the mini-Gα s scaffold with an N-terminus replacement of corresponding sequences of Gα i1 to facilitate the binding of scFv16 3,31,32 , designated as mGα s/q/iN . Unless otherwise stated, G q refers to the mG s/q/iN , which was used for structural studies.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into the peptide selectivity and activation of human neuromedin U receptors

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Zhang

et al. 2022

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Neuromedin U receptors (NMURs), including NMUR1 and NMUR2, are a group of Gq/11-coupled G protein-coupled receptors (GPCRs) related to pleiotropic physiological functions. Upon stimulation by two endogenous neuropeptides, neuromedin U and S (NMU and NMS) with similar binding affinities, NMUR1 and NMUR2 primarily display distinct peripheral tissue and central nervous system (CNS) functions, respectively, due to their distinct tissue distributions. These NMU receptors have triggered extensive attention as drug targets for obesity and immune inflammation. Specifically, selective agonists for NMUR1 in peripheral tissue show promising long-term anti-obesity effects with fewer CNS-related side effects. However, the mechanisms of peptide binding specificity and receptor activation remain elusive due to the lack of NMU receptor structures, which hamper drug design targeting NMU receptors. Here, we report four cryo-electron microscopy structures of Gq chimera-coupled NMUR1 and NMUR2 bound with NMU and NMS. These structures present the conserved overall peptide-binding mode and reveal the mechanism of peptide selectivity for specific NMURs, as well as the common activation mechanism of the NMUR subfamily. Together, these findings provide insights into the molecular basis of the peptide recognition selectivity and offer a new opportunity for designing selective drugs targeting NMURs.

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Section: Resultsmentioning

confidence: 99%

Structural insights into the peptide selectivity and activation of human neuromedin U receptors

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Zhang

et al. 2022

Preprint

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“…The B1 receptor mainly mediates the pain-causing effect of kinin, [ 66 ] while the B2 receptor mainly mediates vasodilation. [ 67 ] Current research suggests that bradykinin acts through G-protein-coupled receptors. [ 68 ] Bradykinin binds to the B2 receptor to stimulate the release of nitric oxide, prostaglandin I2, and endothelium-dependent hyperpolarizing factor, resulting in a strong vasodilation effect.…”

Section: Possible Mechanisms Underlying the Antiarrhythmic Effect Of ...mentioning

confidence: 99%

A narrative review on sacubitril/valsartan and ventricular arrhythmias

Wei

Zhang²,

Zhang³

et al. 2022

Medicine

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Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients.

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“…Endogenous peptides mainly bind to class A and B1 GPCRs 42,43 . Unlike its class B1 counterparts that have large extracellular domains, class A GPCRs usually adopt extended loop conformations during their insertion into the orthosteric pocket by the peptide N terminus [e.g., DAMGO 44 , C-C chemokine ligand 15 (CCL15) 28 , C-X-C motif chemokine ligand 8 (CXCL8) 45 , Aβ 42 46 , N-formyl humanin 46 and ghrelin 36 ], the peptide C terminus [e.g., angiotensin II 47,48 , bradykinin 27 , cholecystokinin-8 (CCK-8) 49 , Des-Arg 10 -kallidin 27 , gastrin-17 25 , IMV449 50 , neuromedin U 51 and neuromedin S 51 ] or the peptide middle region [e.g., α-melanocyte-stimulating hormone (α-MSH) 52 , arginine-vasopressin (AVP) 53 and somatostain-14 54 ], thereby achieving a significantly larger peptide-receptor interface area (>1500 Å 2 ) compared to that displayed by interaction with small molecules (<1000 Å 2 ) (Fig. 5, Supplementary Fig.…”

Section: Class-wide Comparisonmentioning

confidence: 99%

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

Chen

Zhou

Wang

et al. 2022

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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.

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Molecular basis for kinin selectivity and activation of the human bradykinin receptors

Cited by 39 publications

References 48 publications

Structural insights into the peptide selectivity and activation of human neuromedin U receptors

Structural insights into the peptide selectivity and activation of human neuromedin U receptors

A narrative review on sacubitril/valsartan and ventricular arrhythmias

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

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