@AndrasDToth

MD, addicted to receptor pharmacology

Joined May 2020
  • Tweets59
  • Following199
  • Followers66
I am so happy that our paper on the spatiotemporal bias in beta-arrestin signaling is finally out in @scisignal! In this short tweetorial, I would like to sum up the main findings. 🧵doi.org/10.1126/scisignal.ad…
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I am delighted to report that our latest paper has now been published in Science Advances: science.org/doi/10.1126/scia… In this study, we generated and characterised a humanised GLP‑1R mouse model carrying the gain‑of‑function A316T variant using CRISPR/Cas9 knock‑in technology.

In vivo functional profiling and structural characterization of the human GLP1R A316T variant

The GLP1R A316T missense variant displays improved glucose tolerance but impaired pharmacological incretin responses in vivo.

science.org
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Hooray!! The first major product from the lab is out today @Nature. Small molecules that bind the GPCR-transducer interface change G protein subtype selectivity in predictable ways, enabling rational drug design.💥 Check it out! 👉nature.com/articles/s41586-0… 🧵👇

Designing allosteric modulators to change GPCR G protein subtype selectivity

Nature - Studies of the G-protein-coupled receptor NTSR1 show that the G protein selectivity of this receptor can be modified by small molecules, enabling the design of drugs that work by switching...

nature.com
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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.…
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Our new photoaffinity labelling technology (bit.ly/4kiVZ74) is published in @angew_chem. It is more biocompatible, more efficienct, cheaper and easily accessible, even as a late-stage modification. We are working with @EnamineLtd to make it available for the community.

Target Agnostic Photoaffinity Labelling by Sulfonylhydrazones

Sulfonyl hydrazones were identified as new photo-crosslinkers exploiting their base catalyzed low-energy photoactivation that leads to reactive carbenes. The amino acid promiscuity, their usefulness...

onlinelibrary.wiley.com
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András Tóth retweeted
BryanRoth
@zenbrainest26 Feb 2025
We are depositing the following mice to @MMRRC Adgrf5-EGFP-CT-IRES-CRE GPR123- EGFP-CT-IRES-CRE GPR124- EGFP-CT-IRES-CRE GPR125- EGFP-CT-IRES-CRE Gpr133-EGFP-CT-IRES-CRE GPR156-IRES-Cre GPR156-mGL-IRES-Cre GPR75-IRES-Cre Bai1 mGL-CT-IRES-Cre GPRC5A- EGFP-CT-IRES-ERT2-CRE 1/2
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András Tóth retweeted
Arun K. Shukla@arshukla19 Feb 2025
Delighted to share our study on promiscuous chemokine binding at a chemokine receptor, now published in @MolecularCell!!! Molecular basis of promiscuous chemokine binding and structural mimicry at the C-X-C chemokine receptor, CXCR2: Molecular Cell cell.com/molecular-cell/full…

Molecular basis of promiscuous chemokine binding and structural mimicry at the C-X-C chemokine...

Saha et al. present a global fingerprint of C-X-C chemokine promiscuity and selectivity at the C-X-C chemokine receptors and determine cryo-EM structures of the most promiscuous receptor, CXCR2, in...

cell.com
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András Tóth retweeted
Bence Szalai@ben_szalai9 Dec 2024
Receptors are essential for cell communication, yet most comp CCC tools focus on ligand/receptor expression, not receptor activity. To address this, we developed RIDDEN, a model that infers activity for 229 receptors from transcriptomics data. 1/ n biorxiv.org/content/10.1101/… 1/n
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Our perspectives on the various aspects of bias in GPCR function, with a special focus on their relevance to the kidney, have been published in @NatRevNeph. nature.com/articles/s41581-0…
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Astonishingly, differences in beta-arrestin recruitment almost completely disappeared without endocytosis. Since beta-arrestins form stable interaction with AT1R, even at endosomes, we speculated that agonist-specific differences occur endosomally.
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To get a broader picture, @ben_szalai built an ODE-based mathematical model. This model verified the role of ligand k_off and revealed that compartment-specific differences in GPCR phosphorylation/dephosphorylation are crucial for ligand k_off effects to emerge.
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We hope that the improved understanding of biased signaling will aid in the development of better biased compounds.
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Why is that so? Since differences in agonist effects developed over a relatively long time, we hypothesized that receptor endocytosis might account for it. We then checked what happens in the absence of endocytosis.
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We measured the transducer activation profile of various AT1 angiotensin receptor agonists in real time with BRET sensors. We found substantial temporal variance in agonist effects for beta-arrestin recruitment but not for G protein activation.
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A new paper shows that the #endocytosis of #GPCRs such as AT1R can influence biased signaling through #BetaArrestin, suggesting the efficacy of beta-arrestin-binding ligands depends on spatial location as much as on receptor conformation. @semmelweishu scim.ag/7th
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