Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Masureel, Matthieu; Zou, Yang; Picard, L.; Westhuizen, Emma van der; Mahoney, Jacob P.; Rodrigues, João P. G. L. M.; Mildorf, Thomas J.; Dror, Ron O.; Shaw, David E.; Bouvier, Michel; Pardon, Els; Steyaert, Jan; Sunahara, Roger K.; Weis, William I.; Zhang, Cheng; Kobilka, Brian K.

doi:10.1038/s41589-018-0145-x

Cited by 168 publications

(232 citation statements)

References 53 publications

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“…Structures have been determined of many different GPCRs and a number of distinct states have been identified. For example, X-ray crystallography has identified two major structural states of β-adrenoceptors, comprising a number of inactive states 17-19 and a number of active states 6,7,20-22 . In the absence of a G protein, the most thermodynamically stable state of the agonist-bound receptor is very similar to the inactive state, except for a small contraction of the ligand binding pocket.…”

Section: Figmentioning

confidence: 99%

Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

Warne

Nehmé

et al. 2020

Preprint

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36The β 1 -adrenoceptor (β 1 AR) is a G protein-coupled receptor (GPCR) 37 activated by the hormone noradrenaline, resulting in the coupling of the 38 heterotrimeric G protein G s 1 . G protein-mediated signalling is terminated by 39 phosphorylation of the receptor C-terminus and coupling of β-arrestin 1 (βarr1, 40 also known as arrestin-2), which displaces G s and induces signalling through the 41 MAP kinase pathway 2 . The ability of synthetic agonists to induce signalling 42 preferentially through either G proteins or arrestins (biased agonism) 3 is 43 important in drug development, as the therapeutic effect may arise from only 44 one signalling cascade, whilst the other pathway may mediate undesirable side 45 effects 4 . To understand the molecular basis for arrestin coupling, we determined 46 the electron cryo-microscopy (cryo-EM) structure of the β 1 AR-βarr1 complex in 47 lipid nanodiscs bound to the biased agonist formoterol 5 , and the crystal structure 48 of formoterol-bound β 1 AR coupled to the G protein mimetic nanobody Nb80 6 . 49 βarr1 couples to β 1 AR in a distinct manner to how G s couples to β 2 AR 7 , with the 50 finger loop of βarr1 occupying a narrower cleft on the intracellular surface 51 closer to transmembrane helix H7 than the C-terminal α5 helix of G s . The 52 conformation of the finger loop in βarr1 is different from that adopted by the 53 finger loop in visual arrestin when it couples to rhodopsin 8 , and its β-turn 54 configuration is reminiscent of the loop in Nb80 that inserts at the same position. 55 β 1 AR coupled to βarr1 showed significant differences in structure compared to 56 β 1 AR coupled to Nb80, including an inward movement of extracellular loop 3 57 (ECL3) and the cytoplasmic ends of H5 and H6. In the orthosteric binding site 58 there was also weakening of interactions between formoterol and the residues 59 Ser211 5.42 and Ser215 5.46 , and a reduction in affinity of formoterol for the β 1 AR-60 βarr1 complex compared to β 1 AR coupled to mini-G s . These differences provide 61 a foundation for the development of small molecules that could bias signalling in 62 the β-adrenoceptors. 63 64 65Ligand bias arises through differential activation of the G protein pathway 66 compared to the arrestin pathway and has been observed in ligands binding to many 67 different GPCRs such as the µ-opioid receptor 9 , the angiotensin receptor (AT 1 R) 10 68 10 th December 2019 3 and the β-adrenoceptors, β 1 AR and β 2 AR 5,11 . The ligands can show complex 69 pharmacology. For example, carvedilol is an inverse agonist of β 1 AR when G protein 70 activity is measured, but it is a weak agonist of the MAPK pathway activated by 71 βarr1 11 . In contrast formoterol is an agonist of both pathways, but stimulates the βarr1 72 pathway more than the G protein pathway 5 . Current theories favour the hypothesis 73 that GPCRs exist in an ensemble of conformations and that ligands preferentially 74 stabilise specific conformations 12 . This suggests that the conformation of a receptor 75 bound to a h...

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Section: Figmentioning

confidence: 99%

Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

Warne

Nehmé

et al. 2020

Preprint

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“…It would be interesting to investigate the influence of a further elongation of the amide substituent, maybe even targeting the exosite (at the top of the binding pocket where salmeterol reaches). [23] This might constitute a way to introduce selectivity against the B1AR by targeting this more dissimilar region of the two receptors.…”

Section: Sar Resultsmentioning

confidence: 99%

A Focus on Unusual ECL2 Interactions Yields β₂‐Adrenergic Receptor Antagonists with Unprecedented Scaffolds

Scharf

Zimmermann²,

Wilhelm

et al. 2020

ChemMedChem

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The binding pockets of aminergic G protein-coupled receptors are often targeted by drugs and virtual screening campaigns. In order to find ligands with unprecedented scaffolds for one of the best-investigated receptors of this subfamily, the β 2adrenergic receptor, we conducted a docking-based screen insisting that molecules would address previously untargeted residues in extracellular loop 2. We here report the discovery of ligands with a previously undescribed coumaran-based scaffold. Furthermore, we provide an analysis of the added value that Xray structures in different conformations deliver for such docking screens.

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“…Beyond application to the μOR-fentanyl system, our findings also have broader impacts for our understanding on biased signaling in other class A GPCRs. Similarly, subtle changes in the chemical structures of β 2 AR ligands [45] or single residue mutation in the serotonin receptor 5-HT 2B [46] can also alter the biased signaling specificity by these receptors, demonstrating that GPCR signaling specificity can be altered by very minor changes either in the receptor itself or in the chemical structures of the bound ligands.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

Waal

Shi

You

et al. 2019

Preprint

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The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, activates the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. We found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate a mechanism where the n-aniline ring of fentanyl mediates μOR βarrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles. Author SummaryThe global opioid crisis has drawn significant attention to the risks associated with over-use of synthetic opioids. Despite the public attention, and perhaps in-line with the profit-based incentives of the pharmaceutical industry, there is no public structure of mu-opioid receptor bound to fentanyl or fentayl derivatives. A publicly available structure of the complex would allow open-source development of safer painkillers and synthetic antagonists. Current overdose antidotes, antagonists, require natural products in their synthesis which persists a sizable barrier to market and develop better antidotes. In this work we use advance molecular dynamics techniques to obtain the bound geometry of mu-opioid receptor with fentanyl (and derivatives). Based on our in-silico structure, we synthesized and tested novel compounds to validate our predicted structure. Herein we report the bound state of several dangerous fentanyl derivatives and introduce new derivatives with signaling profiles that may lead to lower risk of respiratory depression.

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Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Cited by 168 publications

References 53 publications

Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

A Focus on Unusual ECL2 Interactions Yields β₂‐Adrenergic Receptor Antagonists with Unprecedented Scaffolds

Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

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Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Cited by 168 publications

References 53 publications

Molecular determinants of β-arrestin coupling to formoterol-bound β1-adrenoceptor

Molecular determinants of β-arrestin coupling to formoterol-bound β1-adrenoceptor

A Focus on Unusual ECL2 Interactions Yields β2‐Adrenergic Receptor Antagonists with Unprecedented Scaffolds

Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

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Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

Molecular determinants of β-arrestin coupling to formoterol-bound β₁-adrenoceptor

A Focus on Unusual ECL2 Interactions Yields β₂‐Adrenergic Receptor Antagonists with Unprecedented Scaffolds