Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500

Nagiri, Chisae; Shihoya, Wataru; Inoue, Asuka; Kadji, Francois Marie Ngako; Aoki, Junken; Nureki, Osamu

doi:10.1038/s42003-019-0482-7

Cited by 38 publications

(24 citation statements)

References 44 publications

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“…To measure the constitutive activity of GPCRs, we used the TGFα shedding assay, which measures accumulation of G q/11 and G 12/13 signaling, as described previously 62 , 63 . To detect G i -coupled GPCR, we utilized a chimeric Gα q/i1 subunit consisting of the Gα q backbone and the Gα i1 -derived 6 amino acids at the C-terminus, which is capable of binding to G i -coupled GPCRs and induces G q signaling.…”

Section: Methodsmentioning

confidence: 99%

“…AP-TGFα release was calculated as described previously 63 and the signal in the mock-transfected conditions was set at the baseline. As a positive control for spontaneous Gi-coupled GPCR, we used a M4-DREADD (M4D), which loses affinity to the endogenous ligand acetylcholine, and introduced glutamine mutant at L123 3.43 , which is known to cause constitutive activity in other GPCRs 62 .…”

Section: Methodsmentioning

confidence: 99%

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Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

Chen

Inoue

et al. 2022

Nat Commun

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GPR88 is an orphan class A G-protein-coupled receptor that is highly expressed in the striatum and regulates diverse brain and behavioral functions. Here we present cryo-EM structures of the human GPR88-Gi1 signaling complex with or without a synthetic agonist (1R, 2R)-2-PCCA. We show that (1R, 2R)-2-PCCA is an allosteric modulator binding to a herein identified pocket formed by the cytoplasmic ends of transmembrane segments 5, 6, and the extreme C terminus of the α5 helix of Gi1. We also identify an electron density in the extracellular orthosteric site that may represent a putative endogenous ligand of GPR88. These structures, together with mutagenesis studies and an inactive state model obtained from metadynamics simulations, reveal a unique activation mechanism for GPR88 with a set of distinctive structure features and a water-mediated polar network. Overall, our results provide a structural framework for understanding the ligand binding, activation and signaling mechanism of GPR88, and will facilitate the innovative drug discovery for neuropsychiatric disorders and for deorphanization of this receptor.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

Chen

Inoue

et al. 2022

Nat Commun

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“…Of note, the inverse agonist IRL2500 in the inactive ET B R structure [PDB ID: 6k1q ( 67 )] interacts, in addition to other residues, with an aromatic moiety directly at W336 6.48 in TM6, which is known generally for class A GPCRs to be a crucial trigger for receptor activation. This W 6.48 is located in the CWxP 6.50 motif involved in activation-related TM6 outward movement as part of the “global toggle-switch” activation model ( 81 , 82 ), also described as the “rotamer toggle switch” hypothesis ( 1 , 83 ).…”

Section: Lessons From Inactive State Structuresmentioning

confidence: 99%

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

et al. 2022

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In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

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“…BQ788 [ 85 ], A192621 [ 86 ], and IRL-2500 [ 87 ] are selective ET B receptor antagonists. Nagiri et al suggested that IRL-2500 acts as an inverse agonist by analyzing the structure of the IRL-2500/ET B receptor complex [ 88 ]. However, to date, only a few studies have attempted to examine the roles of ET B receptors in the treatment of diseases.…”

Section: Overview Of Endothelinmentioning

confidence: 99%

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

Kōyama

2021

IJMS

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In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

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Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500

Cited by 38 publications

References 44 publications

Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

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