Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism

Deluigi, M.; Klipp, A.; Klenk, Christoph; Merklinger, L.; Morstein, Lena; Heine, Philipp; Mittl, Peer R. E.; Erñst, Patrick; Kamenecka, Theodore M.; He, Yuanjun; Vacca, Santiago; Egloff, Pascal; Honegger, Annemarie; Plückthun, Andreas

doi:10.1126/sciadv.abe5504

Cited by 46 publications

(100 citation statements)

References 67 publications

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“…In contrast, the negative charge of the shorter Asp150 side chain, as well as the positive charge of Asp328, may play an important role in agonist-induced receptor activation, in agreement with functional characterization of the D150A and R328M mutations in the wild-type receptor. [18] This behavior highlights the complex interplay between various regions in the GPCR that affect its conformational landscape in a cooperative manner. Another important residue in TM86 V that has been mutated in HTGH4 is Ile260.…”

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confidence: 97%

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Probing the Conformation States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling

et al. 2020

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G protein‐coupled receptors (GPCRs) are key players in mediating signal transduction across the cell membrane. However, due to their intrinsic instability, many GPCRs are not suitable for structural investigations. Various approaches have been developed in recent years to remedy this situation, ranging from the use of more native membrane mimetics to protein‐stabilization methods. The latter approach typically results in GPCRs that contain various numbers of mutations. However, probing the functionality of such variants by in vitro and in vivo assays is often time consuming. In addition, to validate the suitability of such GPCRs for structural investigations, an assessment of their conformation state is required. NMR spectroscopy has been proven to be suitable to probe the conformation state of GPCRs in solution. Here, by using chemical labeling with an isotope‐labeled methyl probe, we show that the activity and the conformation state of stabilized neurotensin receptor 1 variants obtained from directed evolution can be efficiently assayed in 2D NMR experiments. This strategy enables the quantification of the active and inactive conformation states and the derivation of an estimation of the basal as well as agonist‐induced activity of the receptor. Furthermore, this assay can be used as a readout when re‐introducing agonist‐dependent signaling into a highly stabilized, and thus rigidified, receptor by mutagenesis. This approach will be useful in cases where low production yields do not permit the addition of labeled compounds to the growth medium and where 1D NMR spectra of selectively 19F‐labeled receptors are not sufficient to resolve signal overlap for a more detailed analysis.

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confidence: 97%

“…For TM86V-BM, an additional inactive state at~23.25 ppm 13 C chemical shift as detected, consistent with a further inward rotation of TM6 at the intracellular side, was also observed in the crystal structures of the antagonist-bound state. [18] e) Visualization of the structural states involved in GPCR activation, adapted from ref.…”

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confidence: 99%

Probing the Conformation States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling

et al. 2020

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“…Moreover, pairwise structural comparison of NMUR1 and NMUR2 reveals potential determinants for receptor subtype selectivity. Additionally, a mechanism of R 6.55 -triggered receptor activation was found, which is conserved by the ghrelin receptor and neurotensin receptor 1 31,47 .…”

Section: Discussionmentioning

confidence: 92%

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

You

Zhang

et al. 2022

Preprint

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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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“…Inferred from the mechanism, antagonists tend to fit in more expanded orthosteric pockets. This was established in different types of class A GPCRs, including lipid receptors [55][56][57][58], peptide receptors [59][60][61], and nucleotide receptors [62][63][64][65].…”

Section: Activation Mechanismmentioning

confidence: 99%

“…in different types of class A GPCRs, including lipid receptors [55][56][57][58], peptide receptors [59][60][61], and nucleotide receptors [62][63][64][65].…”

Section: Activation Mechanismmentioning

confidence: 99%

Ligands of Adrenergic Receptors: A Structural Point of View

Zeng

Zhao

2021

Biomolecules

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Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.

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Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism

Cited by 46 publications

References 67 publications

Probing the Conformation States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling

Probing the Conformation States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling

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

Ligands of Adrenergic Receptors: A Structural Point of View

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