Suweb RezaHarnessing Designer Muscarinic GPCRs for Research
🧩 DREADD technology enables specific signal modulation
#GPCRs #DREADD #Neuroscience #Pharmacology #Science
https://tnyp.me/kGMOwdqN/m #Pub2Post
Harnessing Designer Muscarinic GPCRs for Research
🧩 DREADD technology enables specific signal modulation
#GPCRs #DREADD #Neuroscience #Pharmacology #Science
https://tnyp.me/kGMOwdqN/m #Pub2Post
Evolving GPCRs for Activation by Inert Ligands
🧪 GPCRs activated by inert clozapine-N-oxide
✨ 5 muscarinic ACH receptor subtypes created
🔬 Mimicked parent receptor signaling
🧠 hM4D receptor silenced neurons
#GPCRs #Neuroscience #Biochemistry #Pub2Post https://tnyp.me/kGMOwdqN/m
🧪 GPCRs activated by inert clozapine-N-oxide
✨ 5 muscarinic ACH receptor subtypes created
🔬 Mimicked parent receptor signaling
🧠 hM4D receptor silenced neurons
#GPCRs #Neuroscience #Biochemistry #Pub2Post https://tnyp.me/kGMOwdqN/m
RCNS MedChem Research GroupFollowing our recent review on #fluorescent probes for #GPCRs, our latest paper details an interesting case study of the M2 receptor.
https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.4c00592
https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.4c00592
Our latest review in Eur J Pharm Sci summarizes recent advances (2018–2024) in #fluorescent probe development for Class A #GPCRs, analyzing over 120 newly developed probes covering 60 GPCRs. doi.org/10.1016/j.ejps.2025.107074
PLOS Biology#Lysophosphatidylserine is a lipid signalling molecule implicated in a range of #immune-related processes. This study reveals the mechanism of #LysoPS recognition by two #GPCRs, GPR34 & GPR174, with implications for drug discovery #PLOSBiology https://plos.io/3T9ryVM
Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174
Lysophosphatidylserine (LysoPS) is a lipid signalling molecule implicated in a range of processes related to the immune system. This structural study reveals the mechanism of LysoPS recognition by two G protein-coupled receptors, GPR34 and GPR174, offering insights into lysophospholipid signaling and presenting opportunities for drug discovery.
Martin VögeleSome of my colleagues at Schrödinger recently published a preprint on a robust protocol to dock ligands into GPCR structures (or Alphafold models) and wrote a blog post about it.
Preprint:
https://chemrxiv.org/engage/chemrxiv/article-details/64caab6edfabaf06ff98c583
First preprint about my work at Schrödinger:
We show how to predict ligand efficacy via absolute binding free energy perturbation on different receptor conformations — confirming and utilizing the principle that the functional response of a receptor is mainly determined by the thermodynamics of ligand binding.
https://chemrxiv.org/engage/chemrxiv/article-details/64b1cccaae3d1a7b0db45aa8
#FEP #FreeEnergy #LigandEfficacy #GPCR #DrugDiscovery #DrugDesign #Thermodynamics #GPCRs #BindingFreeEnergy
Is the functional response of a receptor determined by the thermodynamics of ligand binding?
Although strong binding to the target protein is a prerequisite, it is not enough to be an effective drug. To produce a particular functional response, drugs need to regulate the targets’ signal transduction pathways, either blocking the proteins’ functions or modulating their activities by changing the conformational equilibrium. The routinely calculated binding free energy of a compound to its target is a good predictor of affinity but may not always predict efficacy. While the time scales for the protein conformational changes are prohibitively long to be routinely modeled via physics-based simulations, thermodynamic principles suggest that binding free energies of the ligands with different receptor conformations may infer their efficacy if the functional response of the receptor is determined by thermodynamics. However, while this hypothesis was proposed in the past, it has not been thoroughly validated and is seldom used in practice for ligand efficacy prediction. We present an actionable protocol and a comprehensive validation study to show that binding thermodynamics provides indeed a strong predictor for the efficacy of a ligand. We apply the absolute-binding free energy perturbation (ABFEP) method to ligands bound to active and inactive states of eight G protein–coupled receptors (GPCRs) and a nuclear receptor. By comparing the resulting binding free energies, we can determine with a very high accuracy whether a ligand acts as an agonist or an antagonist. We find that carefully designed restraints are often necessary to efficiently model the corresponding conformational ensembles for each state and provide a procedure for setting up these restraints. Our method achieves excellent performance in classifying ligands as agonists or antagonists across the various investigated receptors, all of which are important drug targets.
Gaspar JekelyThe 31 new deorphanized #neuropeptide #GPCRs from #Nematostella and the #phylogenetic trees also allowed us to predict the ligand for many receptors across #cnidarians. We hope that cnidarian researchers will functionally characterising these e.g. by #CRISPR, as the Houliston lab has done for the MIH receptor.
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000614
#evolution #neuroscience
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000614
#evolution #neuroscience
A G protein–coupled receptor mediates neuropeptide-induced oocyte maturation in the jellyfish Clytia
A study of jellyfish oocytes identifies the receptor for Maturation-Inducing Hormone, the neuropeptide hormone that triggers oocyte maturation and spawning via GαS and cyclic AMP. This receptor defines a superfamily of hormone-receptor systems involved in regulating sexual reproduction across animal species.
By phylogenetic reconstruction, Daniel Thiel and Luis Yanez could show that #cnidarian #neuropeptide receptors diversified independent from #GPCRs in bilateria. This parallel #evolution and expansion confirms that cnidarians do not represent the ancestral state in neuronal signalling (as implied by terms like 'pre-bilaterian') any more than bilaterians.
#receptor #evolution #neuroscience #phylogeny
#receptor #evolution #neuroscience #phylogeny