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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
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G-protein Coupled Receptors01:21

G-protein Coupled Receptors

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization
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Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization

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Molecular docking screening using agonist-bound GPCR structures: probing the A2A adenosine receptor.

David Rodríguez1,2,3, Zhang-Guo Gao4, Steven M Moss4

  • 1†Science for Life Laboratory, Stockholm University, Box 1031, SE-171 21 Solna, Sweden.

Journal of Chemical Information and Modeling
|January 28, 2015
PubMed
Summary

Structure-based drug design for the adenosine A2A receptor (A2AAR) faces challenges. Screening large libraries identified ligands but not agonists, highlighting the need for novel strategies for complex targets like A2AAR.

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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Area of Science:

  • Pharmacology
  • Structural Biology
  • Drug Discovery

Background:

  • Crystal structures of G protein-coupled receptors (GPCRs) offer insights into ligand binding and activation for structure-based drug design.
  • The adenosine A2A receptor (A2AAR) is a therapeutic target for cardiovascular diseases, yet lacks novel agonist scaffolds.

Purpose of the Study:

  • To investigate the utility of structure-based screening against active-like A2AAR conformations for discovering novel agonists.
  • To identify challenges and propose strategies for structure-based drug discovery of GPCR agonists.

Main Methods:

  • Docking screens of 6.7 million commercially available molecules against active-like A2AAR conformations.
  • Experimental validation of predicted A2AAR ligands and assessment of their agonist activity.

Main Results:

  • Nine of 20 predicted molecules were confirmed as A2AAR ligands, but none demonstrated agonist activity.
  • Screening library composition, biased towards antagonists, and limited understanding of receptor activation hindered agonist discovery.
  • The complexity of ligand interactions required for A2AAR activation was underestimated by standard library screening.

Conclusions:

  • Structure-based screening of large, biased libraries may be unsuitable for discovering agonists for targets like A2AAR that require complex ligand interactions.
  • Future A2AAR agonist development requires novel scaffolds and refined structure-based strategies.
  • Generalizable strategies for GPCR drug discovery, particularly for complex targets, need further development.