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

The method has found druggable sites overlapping with the cocrystallized allosteric ligands in 21 GPCR have a strong binding hot spot at the same location, suggesting potential allosteric sites in a large However, ligands binding at the same location generally show little or no similarity, and the amino acid residues interacting with these ligands also differ. binding sites among the limited number of potential locations."

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 previously reported intracellular CCR2 antagonists, several tetramethylrhodamine (TAMRA)-labeled CCR2 ligands By means of these studies, we developed 14 as a fluorescent CCR2 ligand, enabling cell-free as well as Thus, our small-molecule-based fluorescent CCR2 ligand 14 represents a promising tool for future studies

They are G-protein-coupled receptors and bind as ligand retinal, which is bound covalently to a lysine This makes opsins light-sensitive. Like those, they have a derived NPxxY motif.

Crystal structures suggest ligand access to the orthosteric binding site of MT1 and MT2 receptors through We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist consistent with the possibility that the gap between TM IV and V is a way of connecting the orthosteric binding site and the membrane core for lipophilic melatonin receptor ligands. pocket on the surface of MT1 receptor, which could participate in the recognition of MT1-selective ligands

A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET Applying this molecular tool in a membrane-based setup and in living cells, we discovered a 4-aminopyrimidine

dual contrasting functional feature of CBD, that is, displaying antagonistic and (possible) agonistic ligand From microsecond-length unbiased molecular dynamics simulations, we found that the presence of the CBD ligand contrast, when the GPR55 receptor is simulated in complex with the selective agonist ML186, agonist-like These results are in agreement with the proposed modulatory function of each ligand, showing that the The all-atom MD simulations reveal that CBD induces conformational changes linked with agonist-bound

their affinity for bound ligands. Here, we investigate the conformational changes induced by the binding of a nanobody (Nb80) on the active-like conformation of the receptor, independent of ligand binding, in contrast to the conditions under which Besides, ligand-specific subtle differences in the conformations assumed by intracellular loop 2 and networks between the Nb80 and the ligand-binding sites, primarily involving residues around ICL2 and

HH binding leads to the dislocation of PTC1 from the cilia, thus making way for SMO to localize in the ciliary membrane models, respectively, to study the interactions of SMO with cholesterol and other lipid domain (CRD) and the intracellular domain (ICD), are through residues belonging to known cholesterol-binding by the presence of multiple cholesterol-binding motifs. Further detailed analysis of the dynamics of the TMD reveals the movements of TM5, TM6, and TM7, linked

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

The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding

Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively

Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question.

October 2022 "Study of small molecule binding to live cells provides important information on the characterization of ligands pharmacologically. Here we developed and validated a label-free, liquid chromatography-mass spectrometry (LC-MS) based cell Competition binding analysis by titration of five known ligands suggested a good correlation with their This versatile method allows quantitative characterization of ligand binding to cell surface expressed

Although YM inhibits wild type αq by binding to αq-GDP and preventing GDP/GTP exchange, the mechanism examined N-terminal mutants of αqQ209L, termed PM-restricted αqQ209L, in which the addition of membrane-binding to βγ and decreased binding to regulator RGS2, and effectors p63RhoGEF-DH/PH and phospholipase C-β. wild type αq is strongly inhibited by YM, demonstrating that resistance to YM inhibition by membrane-binding Together, these results indicate that changes in membrane binding impact the ability of YM to inhibit

HLGR2 RNAi led to a low pupation rate (45.00%), body malformation, abnormal wing expansion, failed cuticle Conclusion: HLGR2 is essential for the growth and development and wing expansion and maturation in H.

October 2022 "Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid 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.

GPCR activation typically occurs through the binding of agonists which stabilize receptor conformations 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 challenges in creating ligands that are both safe and effective. binding sites, the inability to target large and diffuse binding sites activated by peptides or proteins

September 2022 "Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid 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.

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics of ligands We have predicted the absolute ligand residence times on the timescale of seconds. Additionally, we calculated the thermodynamics of ligand binding in terms of ligand binding energies In the experiment, similar sets of residues were found to be in significant contact with both ligands unbinding with the thermodynamics of ligand binding."

Ligands must first partition into the surrounding membrane and take lipid paths to these sites. Remarkably, a significant part of the bound ligands appears exposed to the membrane lipids. to ligand access and binding is often overlooked and poorly understood. The observed differences in the binding affinity and cooperativity arise from the functional groups that interact primarily with lipids.

September 2022 Fly casting with ligand sliding and orientational selection supporting complex formation hETB binding pocket. Last, in the pocket, ligand–receptor attractive native contacts are formed. Eventually, the native-like complex is completed. The ligand-sliding corresponds to overcoming of a free-energy barrier between the basins."

to multiple ligands to regulate key biological functions including neurodevelopment and organogenesis The LK30/ADGRL3 complex structure revealed that the LK30 binding site on ADGRL3 overlaps with the binding site for an ADGRL3 ligand – teneurin. specifically broke the trans-cellular interaction of ADGRL3 with teneurin, but not with another ADGRL3 ligand Our work provides proof of concept for the modulation of isoform- and ligand specific aGPCR functions

September 2022 Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface "Galanin is a neuropeptide expressed in To understand the basis of the ligand preferences of the receptors and to assist structure-based drug Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ2AR was used to relate galanin binding to the movements of

September 2022 "Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation

August 2022 "G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. uncover that the intermediate state complex comprising β1-AR and nucleotide-free Gs is more stable when binding These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins."

However, these conventional assays often provide limited information on intermediate signaling events binding (e.g NanoBRET ligand binding [5]), effector protein recruitment assays (e.g G protein recruitment Moreover, these experiments can be conducted in live cells, preserving the physiological context and BERKY consists of a membrane linker, a BRET donor, an ER/K α-helix linker, a BRET acceptor, and an active Galés, C., et al., Real-time monitoring of receptor and G-protein interactions in living cells. 

central question of GPCR drug discovery is to understand what determines the agonism or antagonism of ligands that bind them. Ligands exert their action via the interactions in the ligand binding pocket. We computationally docked ~2700 known β2AR ligands to multiple β2AR structures, generating ca 75 000 docking poses and predicted all atomic interactions between the receptor and the ligand.