Recent advances in computational studies of GPCR-G protein interactions

Wang, Jinan; Miao, Yinglong

doi:10.1016/bs.apcsb.2018.11.011

Cited by 13 publications

(18 citation statements)

References 117 publications

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“…These regions have been highlighted to be important determinants for specific GPCR-G protein coupling in extensive experimental and computational studies as reviewed earlier. [10][11][12]46 In summary, the GaMD simulations with unconstrained enhanced sampling and free energy calculations have provided important insights into the mechanism of specific G protein coupling to the A1AR and A2AAR. Nevertheless, effects of binding different extracellular ligands (e.g., agonists of varied potencies and allosteric modulators) on the GPCR-G protein interactions are subject to future studies.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

Wang

Miao

2019

Preprint

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Coupling between G-protein-coupled receptors (GPCRs) and the G proteins is a key step in cellular signaling. Despite extensive experimental and computational studies, the mechanism of specific GPCR-G protein coupling remains poorly understood. This has greatly hindered effective drug design of GPCRs that are primary targets of ~1/3 of currently marketed drugs. Here, we have employed all-atom molecular simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method to decipher the mechanism of the GPCR-G protein interactions. Adenosine receptors (ARs) were used as model systems based on very recently determined cryo-EM structures of the A1AR and A2AAR coupled with the Gi and Gs proteins, respectively. Changing the Gi protein to the Gs led to increased fluctuations in the A1AR and agonist adenosine (ADO), while agonist 5'-N-ethylcarboxamidoadenosine (NECA) binding in the A2AAR could be still stabilized upon changing the Gs protein to the Gi. Free energy calculations identified one stable low-energy conformation for each of the ADO-A1AR-Gi and NECA-A2AAR-Gs complexes as in the cryo-EM structures, similarly for the NECA-A2AAR-Gi complex. In contrast, the ADO agonist and Gs protein sampled multiple conformations in the ADO-A1AR-Gs system. GaMD simulations thus indicated that the ADO-bound A1AR preferred to couple with the Gi protein to the Gs, while the A2AAR could couple with both the Gs and Gi proteins, being highly consistent with experimental findings of the ARs. More importantly, detailed analysis of the atomic simulations showed that the specific AR-G protein coupling resulted from remarkably complementary residue interactions at the protein interface, involving mainly the receptor transmembrane 6 helix and the Gα α5 helix and α4-β6 loop. In summary, the GaMD simulations have provided unprecedented insights into the dynamic mechanism of specific GPCR-G protein interactions at an atomistic level, which is expected to facilitate future drug design efforts of the GPCRs.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

Wang

Miao

2019

Preprint

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“…Thus, the dynamic mechanism of specific GPCR–G protein interactions remains poorly understood. To fill this gap, computational approaches have been developed to model the dynamic GPCR–G protein interactions [ 61 , 62 ]. For instance, Flock et al provided a bioinformatics approach to determine a selectivity barcode (patterns of amino acids) of GPCR−G protein coupling [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Höring

Conrad

Söldner

et al. 2021

IJMS

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G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

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“…A second, less extensive interface is established between αN, αN‐β1 hinge, β1, β2‐β3 loop, α5, and ICL2 (Figure S3). In addition, further Gα interactions (α3‐β5 loop, α2, α2‐β4 loop) with the GPCRs are described [24,50,58,60,63] …”

Section: Gαi/s Interfaces: Determinants Of G Protein Signalingmentioning

confidence: 99%

“…Consequently, the Gα C‐terminus is mainly responsible for the affinity and specificity of the G protein‐GPCR interaction [50,65,66] . Beside α5, an impact of αN, the αN‐β1 loop, the α4‐β6 region, and α4 on the specificity of G protein coupling has been suggested, due to specificity determining residues within these regions [24,50] . Furthermore, TM6, ICL2 and ICL3 were related to mediate the coupling selectivity [50,59,61,63] …”

Section: Gαi/s Interfaces: Determinants Of G Protein Signalingmentioning

confidence: 99%

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Strategies towards Targeting Gαi/s Proteins: Scanning of Protein‐Protein Interaction Sites To Overcome Inaccessibility

Nubbemeyer

Pepanian

George³

et al. 2021

ChemMedChem

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Heterotrimeric G proteins are classified into four subfamilies and play a key role in signal transduction. They transmit extracellular signals to intracellular effectors subsequent to the activation of G protein‐coupled receptors (GPCRs), which are targeted by over 30 % of FDA‐approved drugs. However, addressing G proteins as drug targets represents a compelling alternative, for example, when G proteins act independently of the corresponding GPCRs, or in cases of complex multifunctional diseases, when a large number of different GPCRs are involved. In contrast to Gαq, efforts to target Gαi/s by suitable chemical compounds has not been successful so far. Here, a comprehensive analysis was conducted examining the most important interface regions of Gαi/s with its upstream and downstream interaction partners. By assigning the existing compounds and the performed approaches to the respective interfaces, the druggability of the individual interfaces was ranked to provide perspectives for selective targeting of Gαi/s in the future.

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Recent advances in computational studies of GPCR-G protein interactions

Cited by 13 publications

References 117 publications

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Strategies towards Targeting Gαi/s Proteins: Scanning of Protein‐Protein Interaction Sites To Overcome Inaccessibility

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