The European Research Network on Signal Transduction (ERNEST): Toward a Multidimensional Holistic Understanding of G Protein-Coupled Receptor Signaling

Sommer, Monika; Selent, Jana; Carlsson, Jens; Graaf, Chris de; Gloriam, David E.; Keserű, György M; Kosloff, Mickey; Mordalski, Stefan; Rizk, Aurélien; Sotelo, Eddy; Tiemann, Johanna K. S.; Tobin, Andrew B.; Vardjan, Nina; Waldhoer, Maria; Kolb, Peter

doi:10.1021/acsptsci.0c00024

Cited by 18 publications

(12 citation statements)

References 65 publications

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“…More efforts should be done to define best practices and guidelines for simulation data sharing [ 171 ]. Luckily, many researchers work to promote it [ 172 ], and different initiatives are addressing this issue. Several software packages [ 173 , 174 , 175 , 176 ] have been developed to share trajectories by providing online interactive visualization based on the advantages of the WebGL API.…”

Section: Current Challengesmentioning

confidence: 99%

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Torrens‐Fontanals

Stępniewski

Aranda-García

et al. 2020

IJMS

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G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique.

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Section: Current Challengesmentioning

confidence: 99%

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Torrens‐Fontanals

Stępniewski

Aranda-García

et al. 2020

IJMS

Self Cite

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“…The received messages inform cells about the presence or absence of light-sustaining molecules or nutrients in the immediate surroundings, or they deliver messages sent by other cells. Over 1000 human GPCRs have been discovered, and each works differently regarding the signals they receive ( Sommer et al, 2020 ). The new members’ list is growing daily with advances in new techniques, such as cryogenic electron microscopy and crystallography.…”

Section: Introductionmentioning

confidence: 99%

GPCRs: The most promiscuous druggable receptor of the mankind

Alhosaini

Azhar

Alonazi

et al. 2021

Saudi Pharmaceutical Journal

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All physiological events in living organisms originated as specific chemical/biochemical signals on the cell surface and transmitted into the cytoplasm. This signal is translated within milliseconds–hours to a specific and unique order required to maintain optimum performance and homeostasis of living organisms. Examples of daily biological functions include neuronal communication and neurotransmission in the process of learning and memory, secretion (hormones, sweat, and saliva), muscle contraction, cellular growth, differentiation and migration during wound healing, and immunity to fight infections. Among the different transducers for such life-dependent signals is the large family of G protein-coupled receptors (GPCRs). GPCRs constitute roughly 800 genes, corresponding to 2% of the human genome. While GPCRs control a plethora of pathophysiological disorders, only approximately one-third of GPCR families have been deorphanized and characterized. Recent drug data show that around 40% of the recommended drugs available in the market target mainly GPCRs. In this review, we presented how such system signals, either through G protein or via other players, independent of G protein, function within the biological system. We also discussed drugs in the market or clinical trials targeting mainly GPCRs in various diseases, including cancer.

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“…Here, we provide recommendations for the terminology to use or avoid and the minimum requirements to conclude, report and quantify bias in a reproducible fashion. The recommendations are supported by the authoritative organization for pharmacological nomenclature, the International Union of Basic and Clinical Pharmacology (https://iuphar.org), and the COST Action CA18133 ERNEST (European Research NEtwork on Signal Transduction) (Sommer et al, 2020). These are not recommendations for how to perform experiments, but to adopt a common terminology facilitating consistent reporting, joint understanding of what has been done and what were the results, and more comparable research data.…”

Section: Introductionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. Recommendations for GPCR ligand bias

al.¹,

Gloriam²

2021

Preprint

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G protein-coupled receptors modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Notably, depending on which ligand has activated a particular receptor, it can engage different intracellular transducers. This paradigm of ligand-dependent ‘biased signaling’ dictates a need to advance beyond the level of receptors to consider the combined ligand-receptor pair in order to understand physiological signaling. Bias signaling also has the potential to improve medicines by reducing adverse effects. However, this is challenged by inconsistent interpretation of results and lack of commonly agreed guidelines. Here, we present recommended terminology and guidelines to conduct, report and quantify bias in a comparable and reproducible fashion. We expect these recommendations will facilitate a common understanding of experiments and findings across basic receptor research and drug discovery, while the area and the analytical methods to measure bias are still evolving, especially in complex cellular, tissue and organismal systems.

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The European Research Network on Signal Transduction (ERNEST): Toward a Multidimensional Holistic Understanding of G Protein-Coupled Receptor Signaling

Cited by 18 publications

References 65 publications

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

GPCRs: The most promiscuous druggable receptor of the mankind

International Union of Basic and Clinical Pharmacology. Recommendations for GPCR ligand bias

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