August 2022 "Fluorescently labeled ligands are versatile molecular tools to study G protein-coupled receptors Here, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a By means of these studies, we developed 14 as a fluorescent CCR2 ligand, enabling cell-free as well Thus, our small-molecule-based fluorescent CCR2 ligand 14 represents a promising tool for future studies

In all these situations, chemokines interact with seven-transmembrane chemokine-type G protein-coupled (CKRs) that signal via Gαi and 4 official atypical chemokine receptors (ACKRs) which engage in ligand sites, while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand ligands and ultimately affect cell migration  (Cardona, A. CKRs should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand

Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their

Involvement of various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal Chemokine and chemokine receptors are of the most important and effective molecules in MSC trafficking Chemokine/chemokine receptor axes play a pivotal role in the recruitment and oriented trafficking of immune cells both towards and within the CNS and it appears that chemokine/chemokine receptor signaling In this article, we hypothesized that the chemokine/chemokine receptor axes network have crucial and

which include the W6.48xP6.50 motif and the P5.50I3.40F6.44 motif which are located below the 7TM cavity The agonist ligands (CCL5, CCL3, and [6P4]CCL5) bind to the 7TM cavity with their N-termini adopting However, in US28, the factors stabilizing the inactive state of this motif are absent. However, the role of chemokine ligands in activating US28 and ACKR3 cannot be confirmed without inactive-state receptors, which provide insights into the complexity of the chemokine system, involving ligand promiscuity

September 2022 "The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte

At a molecular level, different ligands bind to the same receptor and vice-versa (Marcuzzi et al. 2018 Drug discovery is shifting towards the development of biased ligands, which promote the engagement of Furthermore, both chemokines and receptors can homo- and hetero-oligomerize, impacting receptor/ligand-binding by globular protein ligands, unlike most of the class A GPCRs ligands that are small molecules or short natural ligands, allowing a better molecular fit with the binding pocket (Paolini-Bertrand et al. 2018

Glycosylation and sulfation – N-terminal PTMs on chemokine receptors The interaction of chemokine receptors with their cognate chemokine ligands is generally described by the two-step/two-site model - the first Within the CRS1 ineraction mode, the N-terminal region of chemokine receptors is indispensable for chemokine tyrosine sulfation sites in their N-termini that mediate ligand binding and signaling (Bannert N et receptor biology and pharmacology however the reported effects can vary depending on the receptor-ligand

C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3). We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between

less side effects, and tools to explore the ORs nature and function, various (poly)pharmacological ligand That is, besides classical ligands, a great number of bivalent ligands (i. e. aiming on two distinct OR subtypes), univalent heteromer-selective ligands and bitopic and allosteric ligands have been synthesized The scope of our review is to present the most important of the aforementioned ligands, highlight their

October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric tissue response to a given dose of the hormone or its antagonist depends on receptors that engage the ligand Thus, we need to know much more about the structures of receptor-ligand complexes at high resolution. Constituent structural motifs cooperatively transform ligand selectivity into specific functions, thus conceptualizing the primacy of the 3D structure over individual motifs of receptors.

Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric These forms were stabilized differently by distinct ligands.

Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. structures, combined with computational analyses, provide insights into the unique and complex process of ligand

August 2022 "As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and Here, we present two cryo-electron microscopy structures of CX3CR1-Gi1 complexes in ligand-free and CX3CL1

genes are transmembrane proteins and cytokines, such as viral G protein-coupled receptors (vGPCRs), chemokines , and chemokine-binding proteins. We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from

Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. structures, combined with computational analyses, provide insights into the unique and complex process of ligand

GPCRs are present in a range of conformations, and the binding of a ligand, as well as interactions with GPCR ligands pharmacology The impact of a ligand on a receptor's structure and biophysical attributes , and consequently on the biological response, is referred to as ligand efficacy. of spatio-temporal attributes in signaling is demonstrated in processes like neurotransmission and chemokine with receptor subtypes that exhibit significant similarity in their orthosteric binding sites, such as chemokine

Here, we provide evidence that distal carboxyl-terminal tail (C-tail), but not proximal, phosphorylation of the chemokine receptor CXCR4 specifies βarrestin1 (βarr1)-dependent signaling. We demonstrate by pharmacologic inhibition of GRK2/3-mediated phosphorylation of the chemokine receptor In addition, we show that GPCRs that have similarly positioned C-tail phosphoresidues are also able to However, although necessary for some GPCRs, we found that distal C-tail sites might not be sufficient

signalling amplification and compartmentalization in T cell activation, focusing on the role of CD28, chemokine

October 2022 Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the Chemokine Receptor CXCR3 for Autoimmune Diseases "The chemokine receptor CXCR3 is a seven-transmembrane G-protein-coupled It is activated by the three chemokine ligands CXCL9, CXCL10, and CXCL11 and enables the recruitment The careful structural modifications during the lead optimization phase led to a compound with high biological

September 2022 Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1 ) and its interactions with antagonist and agonist ligands "The CX3C chemokine receptor 1 (CX3CR1), a member of the class A of G Protein-Coupled Receptors (GPCR) superfamily, and its ligand fractalkine characterize the conformational ensemble of the receptor in the presence of its antagonist and agonist ligands the receptor conformational changes and described interactions within its key regions and the bounded ligands

2022 Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C activation of PKC and mutation of rat mGlu5a Ser901, a PKC-dependent phosphorylation site in the receptor C-tail KO cells, and a receptor containing a mutated putative adaptor protein complex 2 (AP-2) interaction motif

August 2022 "Chemokines, a subgroup of cytokines along with their receptors, are involved in various C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled receptor (GPCR), has one identified natural ligand termed stromal-derived factor-1(SDF-1 or CXCL12).

October 2022 Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. " Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

Depending on which ligand activates a receptor, it can engage different intracellular transducers. Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse However, ligand bias is very complex, making reproducibility and description challenging. Here, we provide guidelines and terminology for any scientists to design and report ligand bias experiments receptor research and drug discovery communities continue to advance our understanding and exploitation of ligand

A variety of ligands for CB1 receptors have been developed as promising drug candidates for the treatment receptor in different functional states have significantly improved our molecular understanding of CB1 ligand These advances have paved the way for development of novel ligands for different therapeutic applications review, we describe the structural determinants for modulation of CB1 receptors by different types of ligands

The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the Ligand binding quantified by intrinsic tryptophan fluorescence showed that hTAS1R2-VFT is capable of have deleterious effects on cellular assays, could impact the ability of hTAS1R2-VFT to bind sweet ligands As expected, the ligand affinities of hTAS1R2-VFT were drastically reduced through the introduction of

The method has found druggable sites overlapping with the cocrystallized allosteric ligands in 21 GPCR models of these proteins confirms that the same sites can be identified without the presence of bound ligands Results show that for each of the 21 structures with bound ligands there exist many other GPCRs that However, ligands binding at the same location generally show little or no similarity, and the amino acid residues interacting with these ligands also differ.