Dr. GPCR Ecosystem   -   Newsletter   -   October 2020

  
  

The Dr.GPCR Summit was a success and the FDA approved Travena's Oliceridine

 

  

Hello Readers,
 

Welcome to the October edition of the Dr. GPCR Newsletter! Thank you for subscribing. If you like our newsletter please share it with your colleagues.

The October Dr.GPCR Newsletter is brought to you by :
  
   

Twist Biopharma produces synthetic mAb libraries to focus on effective sequence space and simultaneous screening against multiple targets to help with hard to drug targets such as GPCRs. You can license Twist Biopharma GPCR Libraries or partner with Twist Biopharma to Generate new leads against any GPCR of interest. 

To learn more about Twist Biopharma and hard to target GPCRs subscribe to the Dr.GPCR podcast and listen to our episode with Dr. Aaron Sato, CSO of Twist Biopharma, available on October 28th.

Here's what we've been working on here at Dr.GPCR:

• Dr. GPCR Podcast: We started releasing weekly (or so) podcast episodes. This month stay tuned for podcast episodes with Dr. Bryan Roth, Dr. Arun Shukla, Dr. Fiona Marshall, and Dr. Aaron Sato.  Subscribe today where you listen to podcasts. Tune in, catch up on previous episodes and stay tuned for our next episodes.

• Have questions about GPCRs or are you running in issues in the lab or about the summit? Join us in the Dr. GPCR Club on LinkedIn.

• Did you know you can also become a Dr. GPCR Member? You’ll get your own membership page on DrGPCR.com and much more!

• Did you know that you can support and sponsor Dr.GPCR's efforts to serve the GPCR community?

 

1.Interesting papers published in September 2020

    1.1 Receptor activation and signaling

• Development of Novel 4‐Arylpyridin‐2‐one and 6‐Arylpyrimidin‐4‐one Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor 

• Discovery of novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor Biased Agonists: Diversified Therapeutic-Like vs. Side Effects Profile 

• Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells 

• A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors 

• Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling 

• Arrestin recruitment to CCR5: potent CCL5 analogs reveal differences in dependence on receptor phosphorylation and isoform-specific recruitment bias 

• Angiotensin II type 1 receptor variants alter endosomal receptor–β-arrestin complex stability and MAPK activation 

• 15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling 

• Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling 

• The G-protein βγ subunits regulate platelet function 

• Allosteric activation of proto-oncogene kinase Src by GPCR–beta-arrestin complexes 
     

    1.2 Structural insights of GPCR function

• Analysis of β2AR-Gs and β2AR-Gi complex formation by NMR spectroscopy 

• Structural basis of CXC chemokine receptor 2 activation and signalling 

• Probing the Conformational States of Neurotensin Receptor 1 Variants by NMR Site‐Directed Methyl Labeling 

• Biased agonism at nociceptin/orphanin FQ receptors: a structure activity study on N/OFQ(1-13)-NH2 

• Structural Biology of Human GPCR Drugs and Endogenous Ligands - Insights from NMR Spectroscopy 

• Probing the Y2 Receptor on Transmembrane, Intra- and Extra-Cellular Sites for EPR Measurements 

• Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor 

• Membrane Orientation and Oligomerization of the Melanocortin Receptor Accessory Protein 2 

• Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases 

• Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling 

• Biological role of arrestin-1 oligomerization 

• Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor 

• Structure-Function Analyses of Human Bitter Taste Receptors—Where Do We Stand? 
     

    1.3 GPCRs in neuroscience

• µ-Opioid receptor–induced synaptic plasticity in dopamine neurons mediates the rewarding properties of anabolic androgenic steroids 

• Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors 

• Protease-activated receptor 1 (PAR1) inhibits synaptic NMDARs in mouse nigral dopaminergic neurons 

• Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation 

• GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11 

• Cellular Expression and Functional Roles of All 26 Neurotransmitter GPCRs in the C. elegans Egg-Laying Circuit 

• Critical Impact of Different Conserved Endoplasmic Retention Motifs and Dopamine Receptor Interacting Proteins (DRIPs) on Intracellular Localization and Trafficking of the D2 Dopamine Receptor (D2-R) Isoforms 

• Light-activated neurons deep in the brain control body heat 

• Interplay between cell-adhesion molecules governs synaptic wiring of cone photoreceptors 

• A novel, injury-free rodent model of vulnerability for assessment of acute and preventive therapies reveals temporal contributions of CGRP-receptor activation in migraine-like pain 
     

    1.4 Novel approaches and tools to study GPCR structure and function

• A high-throughput CRISPR interference screen for dissecting functional regulators of GPCR/cAMP signaling 

• An expanded palette of dopamine sensors for multiplex imaging in vivo 

• Mechanistic Insights into Light-Driven Allosteric Control of GPCR Biological Activity 

• PanGPCR: Predictions for Multiple Targets, Repurposing and Side Effects 

• Exploring GPCR‐arrestin interfaces with genetically encoded crosslinkers 

• Novel Fluorescent Ligands Enable Single-Molecule Localization Microscopy of the Dopamine Transporter 

• Serial Crystallography for Structure-Based Drug Discovery 

• A combination of machine learning and infrequent metadynamics to efficiently predict kinetic rates, transition states, and molecular determinants of drug dissociation from G protein-coupled receptors 

• Signaling activations through G-protein-coupled-receptor aggregations 

• Genetically Encodable Fluorescent and Bioluminescent Biosensors Light Up Signaling Networks 

• A Quantitative Proteome Map of the Human Body 

• MicroED structure of the human adenosine receptor determined from a single nanocrystal in LCP 
     

    1.5 Pharmacology and therapeutic applications  

• A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm 

• Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes 

• Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein 

• Therapeutic Opportunities for Repair GPCRs during Intestinal Mucosal Wound Healing 

• Metabolic Effects of Carvedilol Through β-Arrestin Proteins: Investigations in Streptozotocin-Induced Diabetes Rat Model and C2C12 Myoblasts 

• Expression profiles of proton-sensing G-protein coupled receptors in common skin tumors 

• Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer 

• The landscape of GPCR signaling in the regulation of epidermal stem cell fate and skin homeostasis 

• A Thalamic Orphan Receptor Drives Variability in Short-Term Memory 
     

    1.6 Reviews and Book Chapters

• New insights into the functional impact of G protein-coupled receptor oligomerization 

• Therapeutic validation of an orphan G protein‐coupled receptor: The case of GPR84 

• Regulator of G protein signaling 10: Structure, expression, and functions in cellular physiology and diseases 

• SnapShot: β-Arrestin Functions 

• Druggable Lipid GPCRs: Past, Present, and Prospects 

• Druggable Targets in Endocannabinoid Signaling 

• Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors 

• GPCR Dynamics: Structures in Motion 

• Cryo-EM as a powerful tool for drug discovery 

• Illuminating the path to target GPCR structures and functions 

• When antibodies mislead: the quest for validation 

• β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders 

• The Quest for More Effective Analgesics with Reduced Abuse Liability and Fewer Adverse Effects: Promises, Pitfalls, and Future Perspectives of Biased Agonists at Opioid Receptors 
     

2. In the News

• FDA approves first GPCR biased agonist 

• "Shedding new light on GPCR drug discovery with a novel biosensor technology" webinar replay hosted by Genetic Engineering & Biotechnology News! 

• Sosei Heptares announces that a second novel drug candidate from its multi-target drug discovery collaboration with Pfizer has started clinical trials. Achievement of this milestone triggers a payment of $5 million to Sosei Heptares. 

• Sosei Heptares is delighted to announce the publication of a 30th Anniversary Commemorative Booklet to accompany the celebration of the 30th anniversary of the Group’s founding in June 2020. 

• X4 Pharmaceuticals is proud to sponsor International Waldenstrom's Macroglobulinemia Foundation (IWMF)'s global education webinar series to support and educate everyone affected by #Waldenstrom macroglobulinemia (WM). 

• J. Silvio Gutkind, Ph.D., Named Chair of the Department of Pharmacology 

 

3. Conferences 

• 9th GDR meeting where Dr.GPCR will be presenting a 3-minute flash talk. Check out the fantastic program and register today!-  November 6th-9th, 2020

• 3rd ERNEST meeting is this week - October 12 to 14th, 2020