Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A Receptor.

The adenosine A receptor (AAR) belongs to the rhodopsin-like G protein-coupled receptor (GPCR) family, which constitutes the largest class of GPCRs. Partial agonists show reduced efficacy as compared to physiological agonists and can even act as antagonists in the presence of a full agonist. Here, we determined an X-ray crystal structure of the partial AAR agonist 2-amino-6-[(1-imidazol-2-ylmethyl)sulfanyl]-4--hydroxyphenyl-3,5-pyridinedicarbonitrile (LUF5834) in complex with the AAR construct A-PSB2-bRIL, stabilized in its inactive conformation and being devoid of any mutations in the ligand binding pocket.

Crystal structure of adenosine A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction.

The G protein-coupled adenosine A receptor (AAR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an AAR antagonist with ancillary blockade of the AAR subtype. It constitutes a unique chemotype featuring a poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core structure.

Irreversible Antagonists for the Adenosine A Receptor.

Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments.

Single Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A Receptor with Preladenant Conjugates.

The G protein-coupled adenosine A receptor (A AR) is an important new (potential) drug target in immuno-oncology, and for neurodegenerative diseases. Preladenant and its derivatives belong to the most potent A AR antagonists displaying exceptional selectivity. While crystal structures of the human A AR have been solved, mostly using the A -StaR2 protein that bears 9 point mutations, co-crystallization with Preladenant derivatives has so far been elusive.

Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890-Fit for Translation?

Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, G protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such as asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent selective inhibitors of the Gq subfamily of G proteins.

Sensitive LC-MS/MS Method for the Quantification of Macrocyclic Gα Protein Inhibitors in Biological Samples.

The cyclic depsipeptide FR900359 (FR) isolated from the plant and produced by endosymbiotic bacteria acts as a selective Gq protein inhibitor. It is a powerful tool to study G protein-coupled receptor signaling, and has potential as a novel drug for the treatment of pulmonary diseases and cancer. For pharmacokinetic studies, sensitive quantitative measurements of drug levels are required.

Cell-permeable high-affinity tracers for G proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors.

Background And Purpose: G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The G protein subtypes, which are coupled to PLC activation, can act as oncogenes, and their expression was reported to be up-regulated in cancer and inflammatory diseases. G inhibition may be an efficient therapeutic strategy constituting a new level of intervention.