Probing the cooperative mechanism of the μ–δ opioid receptor heterodimer by multiscale simulation

Wang, Longrong; Yuan, Yuan; Chen, Xin; Chen, Jiang‐Fan; Guo, Yanzhi; Li, Menglong; Li, Chuan; Pu, Xuemei

doi:10.1039/c8cp06652c

Cited by 22 publications

(32 citation statements)

References 116 publications

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“…One study revealed high probabilities of interactions between TM1,2 and TM5,6, but also TM4 and TM5 (as well as TM4,5/TM1,2 for heterodimers); TM3 and TM7 were never involved [117]. In opioid receptor heterodimers, additional computer simulations identified TM1/TM2/IC4 complexes and TM3/TM6 complexes as the most likely means of dimerization [118]. So, the consensus of the existing data is that TM1/TM2 may interact with TM5/TM6, while TM 3 and TM7 are never implicated in dimerization, and TM1 and TM4 seem to be dispensable.…”

Section: Prediction 7 Conserved Modules Include the Transmembrane Regions Of The Receptorsmentioning

confidence: 99%

Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Root‐Bernstein¹,

Churchill²

2021

Life

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Cross-talk between opioid and adrenergic receptors is well-characterized and involves second messenger systems, the formation of receptor heterodimers, and the presence of extracellular allosteric binding regions for the complementary ligand; however, the evolutionary origins of these interactions have not been investigated. We propose that opioid and adrenergic ligands and receptors co-evolved from a common set of modular precursors so that they share binding functions. We demonstrate the plausibility of this hypothesis through a review of experimental evidence for molecularly complementary modules and report unexpected homologies between the two receptor types. Briefly, opioids form homodimers also bind adrenergic compounds; opioids bind to conserved extracellular regions of adrenergic receptors while adrenergic compounds bind to conserved extracellular regions of opioid receptors; opioid-like modules appear in both sets of receptors within key ligand-binding regions. Transmembrane regions associated with homodimerization of each class of receptors are also highly conserved across receptor types and implicated in heterodimerization. This conservation of multiple functional modules suggests opioid–adrenergic ligand and receptor co-evolution and provides mechanisms for explaining the evolution of their crosstalk. These modules also suggest the structure of a primordial receptor, providing clues for engineering receptor functions.

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Section: Prediction 7 Conserved Modules Include the Transmembrane Regions Of The Receptorsmentioning

confidence: 99%

Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Root‐Bernstein¹,

Churchill²

2021

Life

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“…10,11 In fact, some computational investigations also found that the asymmetric activations exist for constitutive activations of opioid receptor dimers. 37,39 Taken together, the asymmetric activation should be common for the GPCR dimers, whether it is agonist-induced activation or constitutive activation and whether it is the homodimer or the heterodimer.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation

Lei

Ding

et al. 2019

ACS Chem. Neurosci.

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Metabotropic glutamate receptors of class C GPCRs exist as constitutive dimers, which play important roles in activating excitatory synapses of the central nervous system. However, the activation mechanism induced by agonists has not been clarified in experiments. To address the problem, we used microsecond all-atom molecular dynamics (MD) simulation couple with protein structure network (PSN) to explore the glutamate-induced activation for the mGluR1 homodimer. The results indicate that glutamate binding stabilizes not only the closure of Venus flytrap domains but also the polar interaction of LB2–LB2, in turn keeping the extracelluar domain in the active state. The activation of the extracelluar domain drives transmembrane domains (TMDs) of the two protomers closer and induces asymmetric activation for the TMD domains of the two protomers. One protomer with lower binding affinity to the agonist is activated, while the other protomer with higher binding energy is still in the inactive state. The PSN analysis identifies the allosteric regulation pathway from the ligand-binding pocket in the extracellular domain to the G-protein binding site in the intracellular TMD region and further reveals that the asymmetric activation is attributed to a combination of trans-pathway and cis-pathway regulations from two glumatates, rather than a single activation pathway. These observations could provide valuable molecular information for understanding of the structure and the implications in drug efficacy for the class C GPCR dimers.

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“…We used Nose-Hoover and Parrinello-Rahman coupling algorithms with 1 ps and 5 ps coupling times to maintain the temperature at 310 • K and 1 bar, respectively. LINCS algorithm was used to constrain the bond lengths in hydrogen atoms [65]. The Particle Mesh Ewald (PME) method was used to compute long-range electrostatic interactions [66].…”

Section: Simulation Protocolmentioning

confidence: 99%

In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

et al. 2020

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Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations. In this work, the impact of the splicing factor 3B subunit 1 (SF3B1) K700E mutation, a highly prevalent mutation in various cancer types, is investigated through molecular dynamics simulations. Based on our results, K700E mutation increases flexibility of the mutant SF3B1. Consequently, this mutation leads to i) disruption of interaction of pre-mRNA with SF3B1 and p14, thus preventing proper alignment of mRNA and causing usage of abnormal 3’ splice site, and ii) disruption of communication in critical regions participating in interactions with other proteins in pre-mRNA splicing machinery. We anticipate that this study enhances our understanding of the mechanism of functional abnormalities associated with splicing machinery, thereby, increasing possibility for designing effective therapies to combat cancer at an earlier stage.

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Probing the cooperative mechanism of the μ–δ opioid receptor heterodimer by multiscale simulation

Abstract: The activation-cooperativity of the μ–δ opioid receptor heterodimer was probed by multiscale simulation coupled with a protein structure network.

Cited by 22 publications

References 116 publications

Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation

In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

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