The Molecular Mechanism of P2Y<sub>1</sub> Receptor Activation

Yuan, Shuguang; Chan, H.C.; Vogel, Horst; Filipek, Sławomir; Stevens, Raymond C.; Palczewski, Krzysztof

doi:10.1002/anie.201605147

Cited by 51 publications

(72 citation statements)

References 38 publications

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“…The non‐nucleotide compound MRS2950 ( 11 ) was identified by virtual screening of the modelled receptor orthosteric site (Costanzi, Kumar, Balasubramanian, Harden, & Jacobson, 2012). Another non‐nucleotide compound, BPTU ( N ‐[2‐[2‐(1,1‐dimethylethyl)phenoxy]‐3‐pyridinyl]‐ N ′‐[4‐(trifluoromethoxy)phenyl]urea, 12 ) and its analogues act as an allosteric inhibitors (Gao & Jacobson, 2017; Peng et al, 2018; Wang, Qiao, et al, 2013; Yuan et al, 2016; Zhang, Gao, et al, 2015).…”

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

180

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

180

184

View full text Add to dashboard Cite

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“…Despite the ergodicity of conformational space in the MC simulations, reliable interactive configurations cannot be obtained from the isolated C-terminus without other PGAM1 domains. MD simulations are routinely used computational tools for studying the structural flexibility of macromolecules, as shown previously [40,[47][48][49][50][51][52][53] . To determine the actual dynamic behavior of the C-terminal segment within its surrounding environment, we first performed MD simulations on the apo-PGAM1 models in aqueous solution.…”

Section: Resultsmentioning

confidence: 99%

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle. Using the PONDR-FIT server, we demonstrated that the C-terminal region was intrinsically disordered. We applied the Monte Carlo (MC) method to explore the conformational space of the C-terminus and conducted a series of explicit-solvent molecular dynamics (MD) simulations, and revealed that the C-terminal region is inherently dynamic; large-scale conformational changes in the C-terminal segment led to the structural transition of PGAM1 from the closed state to the open state. Furthermore, the C-terminal segment influenced 2,3-bisphosphoglycerate (2,3-BPG) binding. The proposed swing model illustrated a critical role of the C-terminus in the catalytic cycle through the conformational changes. In conclusion, the C-terminal region induces large movements of PGAM1 from the closed state to the open state and influences cofactor binding during the catalytic cycle. This report describes the dynamic features of the C-terminal region in detail and should aid in design of novel and efficient inhibitors of PGAM1. A swing mechanism of the C-terminal region is proposed, to facilitate further studies of the catalytic mechanism and the physiological functions of its homologues.

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“…However, our study clearly indicates a major impact of ionic strength on the macro level, that is, the functional state of the receptor. A recent study by Yuan et al (2016) has shown that a continuous channel of water molecules inside the receptor protein is an essential feature of the functionally active state of the adenosine A 1 receptor, another class A GPCR that most likely shares a common activation mechanism with the M 2 AChR. Therefore, one might speculate that ionic strength fine-tunes receptor activity by determining the amount of water molecules available within the binding pocket.…”

Section: Discussionmentioning

confidence: 99%

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

et al. 2017

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Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. In this study, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of G protein-coupled receptor activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M acetylcholine receptor as a model. Second, we employ this assay system to show that a dualsteric design principle, that is, molecular probes, carrying two pharmacophores to simultaneously adopt orthosteric and allosteric topography within a G protein-coupled receptor, may represent a novel approach to achieve protean agonism. We pinpoint three molecular requirements within dualsteric compounds that elicit protean agonism at the muscarinic M acetylcholine receptor. Using radioligand-binding and functional assays, we posit that dynamic ligand binding may be the mechanism underlying protean agonism of dualsteric ligands. Our findings provide both new mechanistic insights into the still enigmatic phenomenon of protean agonism and a rationale for the design of such compounds for a G protein-coupled receptor.

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The Molecular Mechanism of P2Y₁ Receptor Activation

Cited by 51 publications

References 38 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

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The Molecular Mechanism of P2Y1 Receptor Activation

Cited by 51 publications

References 38 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

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The Molecular Mechanism of P2Y₁ Receptor Activation