Structural heterogeneity of the μ-opioid receptor’s conformational ensemble in the apo state

Sena, Diniz M.; Cong, Xiaojing; Giorgetti, Alejandro; Kless, Achim; Carloni, Paolo

doi:10.1038/srep45761

Cited by 20 publications

(21 citation statements)

References 56 publications

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“…The receptor experienced numerous intermediate conformations along the deactivation pathway, but without a strong coupling mechanism between the orthosteric and G-protein-binding sites, giving a putative rationale for the experimental difficulties in fully stabilizing the β 2 -AR in the presence of an agonist [70]. In contrast, other MD studies have shown an allosteric communication between the orthosteric site and a conserved polar network of the μOR (opioid receptor μ) [71,72].…”

Section: Gpcr Activation and Signalingmentioning

confidence: 99%

Peeking at G-protein-coupled Receptors Through the Molecular Dynamics Keyhole

2019

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Molecular dynamics is a state of the art computational tool for the investigation of biophysics phenomenon at a molecular scale, as it enables the modeling of dynamic processes, such as conformational motions, molecular solvation and ligand binding. The recent advances in structural biology have led to a bloom in published G-protein-coupled receptor structures, representing a solid and valuable resource for molecular dynamics studies. During the last decade, indeed, a plethora of physiological and pharmacological facets of this membrane protein superfamily have been addressed by means of molecular dynamics simulations, including the activation mechanism, allosterism and, very recently, biased signaling. Here, we try to recapitulate some of the main contributions that molecular dynamics has recently produced in the field.

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Section: Gpcr Activation and Signalingmentioning

confidence: 99%

Peeking at G-protein-coupled Receptors Through the Molecular Dynamics Keyhole

2019

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“…NPxxY is a highly conserved motif for class A GPCRs; it is located in the intercellular region of TM7 and is involved in the activation processes and modifications of | https://doi.org/10.1007/s42452-021-04505-8 a hydrophobic barrier [39]. Experimental data show that mutations in the NPxxY motif of β2AR or bradykinin B2 (B2R) affect coupling with G-proteins, exhibiting phosphorylation, and subsequent sequestration of these receptors [38,[40][41][42].…”

Section: Agonist and Allosteric Modulation Affect Conformations Around N332mentioning

confidence: 99%

Bias-inducing allosteric binding site in mu-opioid receptor signaling

2021

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G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and differentiate G-protein-coupled receptors (GPCR) signaling pathways and how this is transferred into the cell are open questions. Here, using extensive all-atom molecular dynamics simulations, we analyzed the binding recognition process and signaling effects of three prototype μ-OR agonists. Our suggested structural mechanism of biased signaling in μ-OR involves an allosteric sodium ion site, water networks, conformational rearrangements in conserved motifs and collective motions of loops and transmembrane helices. These analyses led us to highlight the relevance of a bias-inducing allosteric binding site in the understanding of μ-OR’s G-protein-biased signaling. These results also suggest a competitive equilibrium between the agonists and the allosteric sodium ion, where the bias-inducing allosteric binding site can be modulated by this ion or an agonist such as herkinorin. Notably, herkinorin arises as the archetype modulator of μ-OR and its interactive pattern could be used for screening efforts via protein–ligand interaction fingerprint (PLIF) studies. Article highlights Agonists and a sodium ion compete for the bias-inducing allosteric binding site that modulates signaling in mu-opioid receptors. Molecular dynamics simulations of the prototype μ-OR agonist suggest a competitive equilibrium involving the agonist and an allosteric sodium ion. Analysis of experimental data from the literature and molecular models provides the structural bases of biased agonism on μ-OR.

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“…However, detailed activation dynamics, especially the mechanism of functional selectivity, are difficult to capture by X-ray crystallography or cryoEM. NMR spectroscopy has proven to be particularly suitable for monitoring subtle dynamic conformational transitions during GPCR activation (Kofuku et al, 2014;Liang et al, 2018;Shimada et al, 2019). MD on the other side has provided insightful details of the potential activation processes (Latorraca et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…To this end, we have established a dual isotope labeling NMR scheme for µOR based on our previous study (Sounier et al, 2015). For the MD, we used the REST2 enhanced sampling scheme (REST2-MD), which has proven efficient in monitoring GPCR activation (Cong et al, 2019;Sena et al, 2017). We studied five chemically distinct µOR agonists ( Figure 1A): DAMGO, a well-characterized µORspecific peptide (Emmerson et al, 1994;Handa et al, 1981); buprenorphine, a semi-synthetic thebaine analogue and partial agonist (Cowan et al, 1977a;Cowan et al, 1977b); BU72, a potent buprenorphine derivative (Neilan et al, 2004); as well as the aforementioned selective agonists, TRV130 and PZM21.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the μ-opioid receptor biased signaling

Sounier

Granier

Maurel

et al. 2021

Preprint

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GPCR functional selectivity whereby a ligand discriminates specific signaling pathways has opened new opportunities for the design of safer drugs. Ligands orchestrate GPCR signaling cascades by modulating the receptor conformational landscape. Our study provides insights into the dynamic mechanism enabling opioid ligands to selectively activate the G protein over the β-arrestin pathways through the μ-opioid receptor (μOR). We combined functional assays in living cells, solution NMR spectroscopy and enhanced-sampling molecular dynamic simulations to identify the specific μOR conformations induced by G protein-selective agonists. In particular, we describe the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains, through conserved motifs in class A GPCRs. Most strikingly, the selective agonists triggered μOR conformational changes in the intracellular loop 1 and helix 8 domains, which may impair β-arrestin binding or signaling. The findings may apply to other GPCR families and provide key molecular information that could facilitate the design of selective ligands.

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Structural heterogeneity of the μ-opioid receptor’s conformational ensemble in the apo state

Cited by 20 publications

References 56 publications

Peeking at G-protein-coupled Receptors Through the Molecular Dynamics Keyhole

Peeking at G-protein-coupled Receptors Through the Molecular Dynamics Keyhole

Bias-inducing allosteric binding site in mu-opioid receptor signaling

Molecular insights into the μ-opioid receptor biased signaling

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