Structural dynamics bridge the gap between the genetic and functional levels of GPCRs

Torrens‐Fontanals, Mariona; Stępniewski, Tomasz Maciej; Gloriam, David E.; Selent, Jana

doi:10.1016/j.sbi.2021.04.005

Cited by 8 publications

(9 citation statements)

References 52 publications

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“…Typically, these methods provide local insights into receptor dynamics depending on the probe placement (e.g., outward movement of the transmembrane helix (TM) 6 upon receptor activation). In this scenario, molecular dynamics (MD) simulations are an excellent complementary approach to the aforementioned experimental setups, with the advantage of combining both high spatial and temporal resolution [ 6 , 11 ]. This technique allows us to simulate the structural motions of a protein in its natural environment.…”

Section: Molecular Dynamics Simulations Provide Insights Into the Dyn...mentioning

confidence: 99%

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Morales-Pastor¹,

Nerín-Fonz²,

Aranda-García³

et al. 2022

IJMS

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Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias.

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Section: Molecular Dynamics Simulations Provide Insights Into the Dyn...mentioning

confidence: 99%

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Morales-Pastor¹,

Nerín-Fonz²,

Aranda-García³

et al. 2022

IJMS

Self Cite

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“…54 X-ray and 6 cryo-EM structures were downloaded from the PDB, and 84 MD trajectories (apo MD simulations of 28 receptors) were downloaded from GPCRmd (). , The combination of static (structures solved by X-ray and cryo-EM) and dynamic (MD frames) representations of the ECL2 was aimed to complement the structural information (and limitations) coming from the different techniques. Indeed, X-ray structures are static snapshots of dynamic systems, and MD simulations may compensate crystal artifacts and provide information about flexibility. ,, To get a first impression of ECL2 flexibility, we performed the RMSD analysis of α-carbon atoms of the MD frames against the corresponding experimental structures (Figure ). In some cases, the MD frames are rather different from the crystallographic conformation (frames with high RMSD values), and including them in the clustering can enrich the structural description.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, Xray structures are static snapshots of dynamic systems, and MD simulations may compensate crystal artifacts and provide information about flexibility. 28,71,72 To get a first impression of ECL2 flexibility, we performed the RMSD analysis of α-carbon atoms of the MD frames against the corresponding experimental structures (Figure 1). In some cases, the MD frames are rather different from the crystallographic conformation (frames with high RMSD values), and including them in the clustering can enrich the structural description.…”

Section: ■ Resultsmentioning

confidence: 99%

Classification Model for the Second Extracellular Loop of Class A GPCRs

Nicoli

Dunkel

Giorgino

et al. 2022

J. Chem. Inf. Model.

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The extracellular loop 2 (ECL2) is the longest and the most diverse loop among class A G protein-coupled receptors (GPCRs). It connects the transmembrane (TM) helices 4 and 5 and contains a highly conserved cysteine through which it is bridged with TM3. In this paper, experimental ECL2 structures were analyzed based on their sequences, shapes, and intramolecular contacts. To take into account the flexibility, we incorporated into our analyses information from the molecular dynamics trajectories available on the GPCRmd website. Despite the high sequence variability, shapes of the analyzed structures, defined by the backbone volume overlaps, can be clustered into seven main groups. Conformational differences within the clusters can be then identified by intramolecular interactions with other GPCR structural domains. Overall, our work provides a reorganization of the structural information of the ECL2 of class A GPCR subfamilies, highlighting differences and similarities on sequence and conformation levels.

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“…Bitter taste receptors (TAS2Rs) belong to class A of G protein‐coupled receptors (GPCRs) superfamily, containing three different subunits (α, β, and γ subunits) (Dijkman et al., 2018). By using the most advanced computing method and available resources, the puzzles about how the protein sequences and structural dynamics determine the function of GPCRs were discussed (Torrens‐Fontanals et al., 2021). The main component of G protein involved in taste transduction is its α‐subunit, gustducin.…”

Section: Flavonoids and Bitter Taste Receptormentioning

confidence: 99%

A comprehensive review of the metabolism of citrus flavonoids and their binding to bitter taste receptors

Yan

Chen

et al. 2023

Comp Rev Food Sci Food Safe

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Citrus is an important source of flavonoids in our daily diet. Citrus flavonoids have antioxidant, anticancer, anti-inflammatory, and cardiovascular disease prevention functions. Studies have shown that some pharmaceutical values of flavonoids may be related to their binding to bitter taste receptors, thus activating downstream signal transduction pathways; however, the underlying mechanism has not been systematically elucidated. In this paper, the biosynthesis pathway and the absorption and metabolism of citrus flavonoids were briefly reviewed, and the relationship between flavonoid structure and bitter taste intensity was investigated. In addition, the pharmacological effects of bitter flavonoids and the activation of bitter taste receptors in combating various diseases were discussed.This review provides an important basis for the targeted design of citrus flavonoid structures to make them more biologically active and more attractive as powerful drugs for the effective treatment of chronic diseases such as obesity, asthma, and neurological diseases.

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Structural dynamics bridge the gap between the genetic and functional levels of GPCRs

Cited by 8 publications

References 52 publications

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Classification Model for the Second Extracellular Loop of Class A GPCRs

A comprehensive review of the metabolism of citrus flavonoids and their binding to bitter taste receptors

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