Molecular insights into the allosteric coupling mechanism between an agonist and two different transducers for μ-opioid receptors

Zhang, Fuhui; Yuan, Yuan; Chen, Yi-Chi; Chen, Jianfang; Guo, Yanzhi; Pu, Xuemei

doi:10.1039/d1cp05736g

Cited by 4 publications

(8 citation statements)

References 87 publications

(110 reference statements)

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“…101,119 Furthermore, the interaction of M3.46 with R3.50 was found to be associated with the G-protein coupling for the class A GPCRs. 80 Interestingly, the residues constituting the shortest pathway in the DAMGO-μOR monomer system are highly consistent with that revealed by a recent aMD study on the DAMGO-μOR-G-protein ternary complex system 69 despite the fact that DAMGO is a balanced μOR agonist. However, it is noted that the initial structure of the MD simulation on the DAMGO-μOR monomer is based on the crystal structure of the DAMGO-μOR-G-protein crystal structure (PDB ID: 6DDE) that represents the G-protein biased conformation, only removing the G-protein.…”

Section: Impact Of the Heterodimerization On The Structural Communica...supporting

confidence: 81%

“…Although its role in the GPCR signaling was rarely reported, mutations of D 1 R showed that the residue at position 8.56 significantly affects the selectivity of the receptor to transducers . Recently, R34.57 (in ICL2) has been reported by MD simulations to be associated with the coupling of μOR with β-arrestin. , Our result further reveals that these key residues found in the GPCR monomer also involve in the signaling of the μOR/δOR heterodimer. In addition, it is worthy to be noted that some residues involved in TM1, TM2, and H8, which present relatively high frequencies in the allosteric network, are not hot spot residues of the dimer interface, suggesting that different residues on the interface conduct distinct functions.…”

Section: Resultssupporting

confidence: 61%

“…Y7.53 belongs to the NPxxY motif, which is conserved in the class A GPCRs and is an important region involved in the activation of class A GPCRs . The importance of Y7.53 for the β-arrestin signaling of AT 1 R and μOR was highlighted recently by MD works. , In the μOR/δOR heterodimer, the signal of DAMGO transmits from the LBP to T2.39. It was indicated that the interaction of T2.39 with R3.50 can stabilize the inactive state of κOR. , Also, MD simulations on the DAMGO-μOR-β-arrestin complex showed that T2.39 forms an interaction with the finger loop of the β-arrestin .…”

Section: Resultsmentioning

confidence: 99%

“…Protein structure network (PSN) was used to calculate the allosteric regulation between given regions, which have been successfully used in many computational works. ,, In PSN, residues are represented as nodes and the interaction between two nodes are characterized as edges. If the proportion of the interaction of two nodes is equal or greater than the given threshold, the interaction of these two nodes will be considered as an edge (vide eq ).…”

Section: Methodsmentioning

confidence: 99%

“…124 The importance of Y7.53 for the β-arrestin signaling of AT 1 R and μOR was highlighted recently by MD works. 69,88 In the μOR/ δOR heterodimer, the signal of DAMGO transmits from the LBP to T2.39. It was indicated that the interaction of T2.39 with R3.50 can stabilize the inactive state of κOR.…”

Section: Impact Of the Heterodimerization On The Structural Communica...mentioning

confidence: 99%

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Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Chen

Yuan

Chen

et al. 2022

J. Chem. Inf. Model.

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GPCRs regulate multiple intracellular signaling cascades. Biasedly activating one signaling pathway over the others provides additional clinical utility to optimize GPCR-based therapies. GPCR heterodimers possess different functions from their monomeric states, including their selectivity to different transducers. However, the biased signaling mechanism induced by the heterodimerization remains unclear. Motivated by the issue, we select an important GPCR heterodimer (μOR/δOR heterodimer) as a case and use microsecond Gaussian accelerated molecular dynamics simulation coupled with potential of mean force and protein structure network (PSN) to probe mechanisms regarding the heterodimerization-induced constitutive β-arrestin activity and efficacy change of the agonist DAMGO. The results show that only the lowest energy state of the μOR/δOR heterodimer, which adopts a slightly outward shift of TM6 and an ICL2 conformation close to the receptor core, can selectively accommodate β-arrestins. PSN further reveals important roles of H8, ICL1, and ICL2 in regulating the constitutive β-arrestin-biased activity for the apo μOR/δOR heterodimer. In addition, the heterodimerization can allosterically alter the binding mode of DAMGO mainly by means of W7.35. Consequently, DAMGO transmits the structural signal mainly through TM6 and TM7 in the dimer, rather than TM3 similar to the μOR monomer, thus changing the efficacy of DAMGO from a balanced agonist to the β-arrestin-biased one. On the other side, the binding of DAMGO to the heterodimer can stabilize μOR/δOR heterodimers through a stronger interaction of TM1/TM1 and H8/H8, accordingly enhancing the interaction of μOR with δOR and the binding affinity of the dimer to the β-arrestin. The agonist DAMGO does not change main compositions of the regulation network from the dimer interface to the transducer binding pocket of the μOR protomer, but induces an increase in the structural communication of the network, which should contribute to the enhanced β-arrestin coupling. Our observations, for the first time, reveal the molecular mechanism of the biased signaling induced by the heterodimerization for GPCRs, which should be beneficial to more comprehensively understand the GPCR bias signaling.

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Section: Impact Of the Heterodimerization On The Structural Communica...supporting

confidence: 81%

Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Impact Of the Heterodimerization On The Structural Communica...mentioning

confidence: 99%

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Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Chen

Yuan

Chen

et al. 2022

J. Chem. Inf. Model.

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Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

Madhu,

Shewani,

Murarka

2024

J. Chem. Inf. Model.

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The molecular basis of receptor bias in G proteincoupled receptors (GPCRs) caused by mutations that preferentially activate specific intracellular transducers over others remains poorly understood. Two experimentally identified biased variants of β 2 -adrenergic receptors (β 2 AR), a prototypical GPCR, are a triple mutant (T68F, Y132A, and Y219A) and a single mutant (Y219A); the former bias the receptor toward the β-arrestin pathway by disfavoring G protein engagement, while the latter induces G protein signaling explicitly due to selection against GPCR kinases (GRKs) that phosphorylate the receptor as a prerequisite of β-arrestin binding. Though rigorous characterizations have revealed functional implications of these mutations, the atomistic origin of the observed transducer selectivity is not clear. In this study, we investigated the allosteric mechanism of receptor bias in β 2 AR using microseconds of all-atom Gaussian accelerated molecular dynamics (GaMD) simulations. Our observations reveal distinct rearrangements in transmembrane helices, intracellular loop 3, and critical residues R131 3.50 and Y326 7.53 in the conserved motifs D(E)RY and NPxxY for the mutant receptors, leading to their specific transducer interactions. Moreover, partial dissociation of G protein from the receptor core is observed in the simulations of the triple mutant in contrast to the single mutant and wild-type receptor. The reorganization of allosteric communications from the extracellular agonist BI-167107 to the intracellular receptor−transducer interfaces drives the conformational rearrangements responsible for receptor bias in the single and triple mutants. The molecular insights into receptor bias of β 2 AR presented here could improve the understanding of biased signaling in GPCRs, potentially opening new avenues for designing novel therapeutics with fewer side-effects and superior efficacy.

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Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR

Chen,

Wang,

Chen

et al. 2024

Nat Commun

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Molecular insights into the allosteric coupling mechanism between an agonist and two different transducers for μ-opioid receptors

Abstract: G protein-coupled receptors (GPCRs) as the most important class of pharmacological targets regulate G-protein and β-arrestin-mediated signaling through allosteric interplay, which are responsible for different biochemical and physiological actions like...

Cited by 4 publications

References 87 publications

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR

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Molecular insights into the allosteric coupling mechanism between an agonist and two different transducers for μ-opioid receptors

Abstract: G protein-coupled receptors (GPCRs) as the most important class of pharmacological targets regulate G-protein and β-arrestin-mediated signaling through allosteric interplay, which are responsible for different biochemical and physiological actions like...

Cited by 4 publications

References 87 publications

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

Biased Signaling in Mutated Variants of β2-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR

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Resources

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Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations