G‐Protein‐Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State

Bhattarai, Apurba; Wang, Jinan; Miao, Yinglong

doi:10.1002/jcc.26082

Cited by 36 publications

(29 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the case of β2AR, it has been shown that zinc can also modulate the receptor, regulating orthosteric ligand binding or the effect of the agonist [ 49 , 50 ]. The role of lipids in GPCR function has been increasingly recognized, and simulations show their influence in receptor′s dynamics and activation [ 51 , 52 , 53 , 54 , 55 ]. In particular, cholesterol can not only modify physical properties of the membrane, but also directly bind to the receptor.…”

Section: Discussionmentioning

confidence: 99%

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

Renault

Giraldo

2020

IJMS

View full text Add to dashboard Cite

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.

show abstract

Section: Discussionmentioning

confidence: 99%

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

Renault

Giraldo

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…More recently, for the A 1 AR two inactive antagonist-bound structures [24,38] and a cryo-EM active agonist-bound structure [39] were released, so more reliable molecular modeling studies are now possible. Recently, GaMD investigated the flexibility profile of the active adenosine-bound and inactive PSB36-bound A 1 AR [97]. In both simulations, conformations of the ECL2 region and the intracellular end of TM6 fluctuated, with higher flexibility of these receptor portions and of the intracellular end of TM5 in the active state.…”

Section: Activation and Deactivationmentioning

confidence: 99%

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Salmaso

2020

Biomolecules

View full text Add to dashboard Cite

Molecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs). Experimental structures and homology modeling have proven to be useful in understanding and predicting structure activity relationships (SAR) of agonists and antagonists. This review provides an excursus on molecular dynamics (MD) simulations applied to ARs and P2YRs. The binding modes of newly synthesized A1AR- and A3AR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of A3AR affinity. P2Y12R and P2Y1R crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2Y14R antagonists and a large group of allosteric and orthosteric antagonists of P2Y1R, an antithrombotic and neuroprotective target. MD of A2AAR (an anticancer and neuroprotective target), A3AR, and P2Y1R has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward A2AAR and P2Y1R binding sites have also been explored. A1AR, A2AAR, and A3AR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an A3AR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through A2AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.

show abstract

“…Моделирование молекулярной динамики широко применяется для компьютерного конструирования лекарственных средств (CADD) [110,111]. Силовые поля для малых молекул имеют решающее значение, поскольку они не только являются элементами в процессе разработки силовых полей для более крупных биомолекул, но также представляют собой модельные соединения, которые переносятся в лиганды, используемые в CADD.…”

Section: метод молекулярной динамикиunclassified

Basic concepts and physical-chemical phenomena, that have conceptual meaning for the formation of systemic clinical thinking and formalization of the knowledge of systemic structural-functional organization of the human’s organism

Poberezhnyi

Марчук

Katilov

et al. 2020

PMJUA

View full text Add to dashboard Cite

From the point of view of perception and generalization processes there are complex, logic and conceptual forms of thinking. Its conceptual form is the highest result of interaction between thinking and speech. While realizing it, human uses the concept, which are logically formed thoughts, that are the meaning of representation in thinking of unity of meaningful features, relations of subjects or phenomena of objective reality. Special concepts, that are used in the science and technique are called terms. They perform a function of corresponding, special, precise marking of subjects and phenomena, their features and interactions. Scientific knowledge are in that way an objective representation of material duality in our consciousness. Certain complex of terms forms a terminological system, that lies in the basis of corresponding sphere of scientific knowledge and conditions a corresponding form and way of thinking. Clinical thinking is a conceptual form, that manifests and represents by the specialized internal speech with gnostic motivation lying in its basis. Its structural elements are corresponding definitions, terms and concepts. Cardinal features of clinical systems are consistency, criticality, justification and substantiation. Principles of perception and main concepts are represented in the article along with short descriptions of physical and chemical phenomena, that have conceptual meaning for the formation of systematic clinical thinking and formalization of systemic structural-functional organization of the human’s organism

show abstract

G‐Protein‐Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State

Cited by 36 publications

References 64 publications

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Basic concepts and physical-chemical phenomena, that have conceptual meaning for the formation of systemic clinical thinking and formalization of the knowledge of systemic structural-functional organization of the human’s organism

Contact Info

Product

Resources

About